The people behind the papers – Juan Yang and Xuanmao Chen

In mammalian embryos, brains develop from the inside out, with younger neurons moving to the outer layers in a process called radial migration. A new paper in Development finds that, during postnatal development, some of the neurons in the outer layers of the brain undergo a ‘reverse movement’, repositioning themselves by moving in the opposite direction to the initial radial migration. To learn more about the story behind the paper, we caught up with first author Juan Yang and corresponding author Xuanmao Chen, Associate Professor of Neurobiology at the University of New Hampshire (UNH), USA.

Xuanmao, what questions are your lab trying to answer?

Xuanmao: We pursue three major questions. First, we investigate how ciliary signalling modulates postnatal neurodevelopment and neuronal function, thereby influencing learning and memory formation. Second, we are intrigued by how a subset of excitatory neurons in the cerebral cortex are recruited to encode and store associative memory, and how a neuronal activity hierarchy in the brain is developed and maintained. Third, inspired by our recent progress, we seek to understand the evolutionary mechanisms, other than neurogenesis, that underly biological intelligence.

Juan, how did you come to work in the lab and what drives your research today?

Juan Yang: I first became interested in laboratory research during my undergraduate studies, particularly in my molecular biology class, where I was fascinated by how gene expression regulates organismal development and function. To pursue this interest, I joined the Hu lab at the Oilcrops Research Institute, Chinese Academy of Agricultural Sciences, to study how the LAZY gene regulates branching angle formation in rapeseed. I spent countless hours performing PCR for plant genotyping but genuinely enjoyed working in the lab and felt a thrill every time I saw DNA bands appear on an electrophoresis gel. After graduation, I was fortunate to obtain a technician position in the Shen lab at ShanghaiTech University, China, where I became fascinated by using cutting-edge tools such as optogenetics and fibre photometry to investigate how specific neural circuits control the body’s homeostasis. These combined experiences sparked my passion for neuroscience and guided me to pursue my PhD dissertation research in the Chen lab at UNH, where I study neuronal primary cilia and cellular mechanisms underlying postnatal brain development.

What was known about neurodevelopment before you started the project?

Juan Yang & Xuanmao:  It is well-established that pyramidal neurons in the cerebral cortex migrate from the neurogenic regions toward the cortical or hippocampal plate an inside-out manner. Before we started the project, we had thought that pyramidal neurons only undergo unidirectional migration, and the “terminal translocation” of radial migration is viewed as the final step for neuronal placement.

Can you give us the key results of the paper in a paragraph?

Juan Yang & Xuanmao: We discovered that primary cilia of early- and late-born principal neurons in compact layers in the mouse brain, such as the hippocampus CA1 region, display opposite orientations, while primary cilia of principal neurons in loose laminae, including the subiculum, entorhinal cortex, neocortex, and cingulate cortex, are predominantly oriented toward the pia. However, specific cilia directionality was not observed in astrocytes and interneurons in the cerebral cortex, or neurons in nucleated brain regions. Guided by this clue, we found that the cell bodies of principal neurons in inside-out laminated regions, including the hippocampal CA1 region and the neocortex, undergo a slow “reverse movement” for postnatal positioning. Our evidence indicates that it is the reverse movement during early postnatal development that leads to the primary cilia of pyramidal neurons to predominately orient toward the pia. Therefore, the “terminaltranslocation” of radial migration is not the last step, pyramidal neurons in the postnatal cerebral cortex continue to adjust their position and move inwards. The reverse movement must be important for constructing sparsely layered inside-out laminae and for forming sulci (grooves) in the mammalian brain.

Why did you decide to focus on primary cilia? 

Xuanmao: I initially studied type 3 adenylyl cyclase (AC3) during my postdoc training in the Storm Lab at the University of Washington, USA. AC3 is a cilia-specific cyclase originally identified in olfactory cilia. AC3 is known to be essential for olfactory perception in mammals. My first project was to study the role of AC3 in airflow-mediated mechanosensation of olfactory cilia (Chen et al., 2012). Cilia dysfunction is associated with numerous brain disorders in humans, and AC3 was found to be highly enriched in neuronal primary cilia throughout the brain (Bishop et al., 2007). However, the functions of AC3 and neuronal primary cilia in the brain are largely unknown (Guemez-Gamboa et al., 2014). The significance of these unanswered questions prompted me to study neuronal primary cilia in the central nervous system. Years later, it is the intriguing cilia directionality of pyramidal neurons marked by an AC3 antibody that guided the lab to make a breakthrough in the context of postnatal neurodevelopment.

What implications does your work have for understanding human brain evolution?

Xuanmao: In my opinion,the mammalian cerebral cortex, particularly the primate neocortex, can be likened to a “library” consisting of numerous shelves and layers of “books” (excitatory principal neurons). The development of such a sparsely layered, matrix-like architecture and its evolution from the allocortices of lower vertebrates (amphibians or reptiles) to the neocortex of humans not only involves increased neurogenesis (Florio and Huttner, 2014; Rakic, 2009; Taverna et al., 2014) and sufficient accommodating space but also requires fast, long-distance neuronal migration (Nadarajah et al., 2001) and slow, fine-tuned repositioning for final neuronal placement. These processes, particularly the slow repositioning step, permit orderly neuronal maturation and progressive circuit formation, and allow the brain to acquire external information during postnatal development to gradually construct well-organized neural circuitry to enable efficient information processing, storage and retrieval. 

Upon the completion of fast radial migration, the outer layer in the cerebral cortex is highly condensed. It is unclear how the mammalian neocortical structures gradually become loosely layered, while allocortical regions remain highly compact. I believe that an additional step of reverse movement is needed for constructing the sparse 6-layered neocortex. Without reverse movement, only tightly compact 3-layered laminae can be made. Without reverse movement, neuronal maturation in the hippocampal CA1 and neocortex might occur simultaneously (as occurs in the CA3 region)(Yang et al., 2024), rather than following a sequential pattern. Therefore, the reverse movement of pyramidal neurons must be crucial for the evolutionary transition from the 3-layer allocortex to 6-layer neocortex. It is also linked to the gyrification process in gyrencephalic animals, because we discovered that a sulcus is formed, at least in part, via reverse movement.

When doing the research, did you have any particular result or eureka moment that has stuck with you?

Juan Yang & Xuanmao: The Chen lab has been intrigued by the directionality of primary cilia for many years, having observed interesting cilia orientation patterns in multiple peripheral tissues and many cortical regions. We noticed a striking alignment of cilia in the mouse hippocampus at postnatal day 14 (P14), with most pointing in the same direction. However, within the thin stratum pyramidale (SP) of the CA1 region, we observed a small subset of cilia oriented in the opposite direction. This orientation pattern was absent at other developmental stages. We did not know how to interpret this phenomenon, and the question lingered in our minds for several years. One day at home, while casually browsing hippocampus-related articles, Juan Yang came across a review article by Soltesz and Losonczy (Soltesz and Losonczy, 2018), from which she learned that the hippocampal SP contains two distinct neuronal populations: early-born and late-born neurons. This paper inspired her to speculate that the opposing cilia orientations in the CA1 SP likely belong to two distinct groups of neurons. Yang then sent the review paper to Chen in an email explaining her hypothesis. After reading the review paper a few days later, Chen responded: “That makes sense and let’s verify it”. This was the first eureka moment in advancing our understanding on cilia directionality.

The concept of reverse movement could not have been developed if the lab had only used wild-type (WT) mice to assess cilia orientations. In the WT hippocampal CA1 region, the primary cilia of pyramidal neurons are not very long (5-8 µm), and they protrude out of the plasma membrane within a short two-day window (P9–P11), by which point centrioles are no longer clustered at the bottom edge of the SP. Fortunately, the lab also maintained Arl13b-mCherry, Centrin2-GFP double transgenic (Arl13b+) mice (Bangs et al., 2015; Higginbotham et al., 2004), which mark primary cilia and centrioles, respectively. The transgenic mice have much longer cilia (~16 µm) in the CA1 region than the WT mice. They also express cilia a few days earlier than WTs and have a prolonged ciliation time-window spanning from P3 to P14. This extended period provided us with more snapshots to track the cilia and centriole positioning process as well as cell body movement during early postnatal development. For example, at P7 in Arl13b+ mice, early-born neurons have already emanated long cilia, which are largely oriented toward the stratum oriens (SO), whereas late-born neurons are only just beginning to protrude cilia, which are enriched in the bottom edge of the SP and orient toward the stratum radiatum (SR) (Figure 1, top panel). This striking contrast instantly led Chen to formulate a concept of reverse movement, in which late-born neurons first migrate to the bottom edge of the SP before moving back to the main part of the SP. Recognizing the existence of this reverse process was the second key step in advancing this research. Subsequently, we found that slow reverse movement is a common positioning step for most of pyramidal neurons in the cerebral cortex.

The lab also housed a Ift88 conditional knockout (KO) mouse strain (Haycraft et al., 2007), which lacks primary cilia on the excitatory neurons and astrocytes in the forebrain. Notably, Ift88 cKO mice produce a lot more late-born neurons than WTs. The overcrowding of late-born neurons in the outermost cortical layer of Ift88 cKOs gradually leads to the formation of a sulcus via a reverse movement (Figure 1, bottom panel). This observation indicates that principal neurons are subject to backward movement for postnatal repositioning, sometimes individually if the outermost layer is not very crowded, and sometimes collectively if too crowded.  

And what about the flipside: any moments of frustration or despair?

Juan Yang: The challenges of scientific research are numerous, but for me, they gradually fade away – either forgotten over time or overshadowed by new research progress and gaining recognition from my peers.

Why did you choose to submit this paper to Development?

Juan Yang & Xuanmao: Development has a long-standing reputation as a leading peer-reviewed scientific journal focused on developmental biology. We rely on the editorial board’s expertise in neurodevelopment and professionalism to evaluate the significance of our discoveries.

Where will this story take your lab next?

Xuanmao: This story opens multiple new avenues to explore. The lab is well positioned to address the following questions: (1) what key factors control cilia directionality and the reverse movement of principal neurons, and consequently neuronal maturation; (2) how primary cilia regulate or stabilize neuronal positioning; (3) how reverse movement impacts the cortical evolution of mammals; and (4) how neuronal primary cilia modulate neuronal function, contributing to associative learning and memory formation.

Finally, let’s move outside the lab – what do you like to do in your spare time?

Juan Yang: I enjoy playing table games, exploring new cuisines and traveling.

Xuanmao: In the summer, I enjoy spending time with friends and family, swimming and paddling on lakes and beaches. Fall is my favourite time for hiking and admiring the vibrant maple leaves in the mountains. In winter, I love skiing with the kids. The most rewarding activity in my spare time is thinking freely without set objectives and sketching on whiteboards – a hobby that I call “whiteboard fun”.

References:

Bangs, F.K., N. Schrode, A.K. Hadjantonakis, and K.V. Anderson. 2015. Lineage specificity of primary cilia in the mouse embryo. Nat Cell Biol. 17:113-122.

Bishop, G.A., N.F. Berbari, J. Lewis, and K. Mykytyn. 2007. Type III adenylyl cyclase localizes to primary cilia throughout the adult mouse brain. J Comp Neurol. 505:562-571.

Chen, X., Z. Xia, and D.R. Storm. 2012. Stimulation of electro-olfactogram responses in the main olfactory epithelia by airflow depends on the type 3 adenylyl cyclase. J Neurosci. 32:15769-15778.

Florio, M., and W.B. Huttner. 2014. Neural progenitors, neurogenesis and the evolution of the neocortex. Development. 141:2182-2194.

Guemez-Gamboa, A., N.G. Coufal, and J.G. Gleeson. 2014. Primary cilia in the developing and mature brain. Neuron. 82:511-521.

Haycraft, C.J., Q. Zhang, B. Song, W.S. Jackson, P.J. Detloff, R. Serra, and B.K. Yoder. 2007. Intraflagellar transport is essential for endochondral bone formation. Development. 134:307-316.

Higginbotham, H., S. Bielas, T. Tanaka, and J.G. Gleeson. 2004. Transgenic mouse line with green-fluorescent protein-labeled Centrin 2 allows visualization of the centrosome in living cells. Transgenic Res. 13:155-164.

Nadarajah, B., J.E. Brunstrom, J. Grutzendler, R.O. Wong, and A.L. Pearlman. 2001. Two modes of radial migration in early development of the cerebral cortex. Nat Neurosci. 4:143-150.

Rakic, P. 2009. Evolution of the neocortex: a perspective from developmental biology. Nat Rev Neurosci. 10:724-735.

Soltesz, I., and A. Losonczy. 2018. CA1 pyramidal cell diversity enabling parallel information processing in the hippocampus. Nat Neurosci. 21:484-493.

Taverna, E., M. Gotz, and W.B. Huttner. 2014. The cell biology of neurogenesis: toward an understanding of the development and evolution of the neocortex. Annu Rev Cell Dev Biol. 30:465-502.

Yang, J., S. Mirhosseiniardakani, L. Qiu, K. Bicja, A. Del Greco, K. Lin, M. Lyon, and X. Chen. 2024. Cilia Directionality Reveals a Slow Reverse Movement of Principal Neurons for Postnatal Positioning and Lamina Refinement in the Cerebral Cortex. BioRxiv 473383v7.

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To accompany the Biologists @ 100 conference, we have partnered with FocalPlane to bring to you an image competition.

We have now shortlisted 15 images, which will be presented in our gallery at Biologists @ 100 at ACC Liverpool, 24-27 March 2025, and online on the Node and FocalPlane.

Conference attendees will be able to see the images in our gallery and vote in person; for those online, you can browse through the gallery below and vote for your favourite in the poll at the bottom of this post. We’ll add up the votes from the Node, FocalPlane and our conference delegates, and the winner will be announced on Thursday 27 March.

Please vote for your favourite image at the bottom of the page. The voting will close on Wednesday 26 March 11:59pm GMT.

Browse through the gallery (click to expand the images)

Voting is now closed. Thank you to everyone who voted!

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The 3^rd Crick-Beddington Symposium, in memory of Rosa Beddington FRS (1956-2001), took place on 10^th-11^th February at the Francis Crick Institute, London. Rather than providing a broad summary of the event, I decided to embody the ‘Node correspondent’ persona and approach poster presenters to interview them about their research.

The symposium was very well attended, and as a result the posters were distributed across two different areas. On the lunch break of the first day, I made my way over to the quieter poster area, hoping to find a scientist willing to take part in a recorded conversation without too much background noise. Alas, enthusiasm for science was all around in the form of loud, animated discussion, which made my mission challenging!

The first poster to catch my eye was presented by Dr Hocine Rekaik, who was luckily more than happy to take part. Hocine is a postdoc in the lab of Denis Duboule at College de France, Paris. The lab is interested in the function of Hox genes in vertebrate body axis development, of which the sequential activation provides the axial and paraxial tissues with positional information along the anteroposterior axis. Hox genes exhibit temporal and spatial collinearity, which means that for each gene, the timing of expression and the anteroposterior expression domain is linked to its location on the chromosome. This sequential activation, often referred to as the Hox timer, has been extensively studied in vertebrate model systems. However, the precise mechanisms linking gene expression onset with axis elongation remain elusive.

Mice, along with humans and chickens, possess four Hox gene clusters. Hocine explained that, due to the high degree of redundancy, the ideal experiment would involve deleting all of them, yet this is not possible in the mouse. Instead, they turn to the gastruloid, an embryonic stem cell (ESC)-derived model that recapitulates many aspects of gastrulation and axis elongation. Hocine explained, “These gastruloids, when they elongate, they implement the collinear expression of Hox genes, so these are really nice models to study their function and temporal expression”, which is mirrored in the gastruloid as in the embryo. Conveniently, the mouse ESCs used to create them can be modified beforehand to create a mutant line that lacks all four Hox clusters – the Hox-less clone.

Surprisingly, the Hox-less gastruloids elongate and exhibit the same anteroposterior patterning as normal, so to delve deeper into the differences between mutant and wild-type, Hocine and his colleagues performed a single cell RNA-Seq experiment. They found that at 96h and 120h of development, the Hox-less gastruloids were lacking two cell types: definitive endoderm and pharyngeal mesoderm, both of which arise from the anterior primitive streak. Yet the expression of anterior primitive streak genes was unaffected, suggesting that the streak forms as normal but its anterior derivatives are dependent on Hox expression. In accordance with this, CER1 – a crucial gene for anterior development – was significantly downregulated in the mutants. CER1 is expressed in the anterior endoderm, but also as a characteristic stripe in the newly-formed somites.

While gastruloids do express somite marker genes, they don’t exhibit the segmentation that is characteristic of somitogenesis – unless they are placed in Matrigel. “Normal gastruloids have this smooth elongation, but in Matrigel, they start to form this segmented structure” he described, and later went on to explain that this is because the Matrigel provides an extracellular matrix, which allows the cells to polarise, causing the somites to condense and epithelialise. I was surprised to learn that gene expression with and without Matrigel is the same, but Matrigel drastically changes the morphology. Hocine found that the Hox-less gastruloids tended to have fewer somites than wild-type controls, because most of them would form temporarily, then disaggregate. This was accompanied by extrusions developing at the posterior end. A pseudo-time analysis showed that the posterior somite-forming cells – derived from neuromesodermal progenitors (NMPs) – didn’t pass through all the usual cell states on their way to becoming somites, leading to the development of posterior extrusions. Hocine puts this down to the absence of the Hox clock, suggesting “there is no control over the differentiation process, so the cells start to differentiate directly – there is no gatekeeper”. However, no markers of mature, epithelialised somites were ever found in these Hox-less gastruloids.

One explanation Hocine proposed relies on the observation in the embryo that the first, most anterior somites do not give rise to segmented structures and instead, contribute to the muscles of the head, rather than the vertebrae. This region corresponds to the most anterior limit of Hox gene expression, explaining why the anterior somitic tissue is produced as normal – through disaggregation, it is simply undergoing its natural lifecycle. On the other hand, the more posterior, NMP-derived somitic tissues in altered gastruloids may have an altered trajectory and do not develop into the trunk-like mature somites seen in the control.

What’s next for Hocine’s research? He stressed that there is more work to do to understand the changes in gene expression brought about by the absence of the Hox timer. But he is excited for future experiments involving the Hox-less cell line and knows it will be very useful for the lab. They plan to do further experiments to find out how other tissues are affected, especially those involved in axial elongation, like the neural tube.

You can read Hocine’s latest article here:

Rekaik, H. et al. (2023) ‘Sequential and directional insulation by conserved CTCF sites underlies the Hox timer in stembryos’, Nature Genetics, 55(7), pp. 1164–1175. Available at: https://doi.org/10.1038/s41588-023-01426-7.

Stay tuned for more poster interviews coming soon!

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Join us in Athens 3-4 April 2025 for an unforgettable symposium, as global leaders in stem cell research come together to explore groundbreaking advancements in neural stem cells. From development to aging, disease, and repair, this event will dive deep into the complexities of stem cell plasticity, epigenetics, metabolism, and more. With a focus on neuron-glia interactions and brain disease modeling, this symposium offers a unique opportunity to connect, learn, and push the boundaries of science. Don’t miss out on this exciting event that promises to shape the future of neural research!

Visit our webpage to learn more and register today!

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In this SciArt profile, we meet Harsh Kapoor, who has a background in genetics and molecular biology, but decided to switch gears from doing a PhD to starting his own visual science communication company.

Can you tell us about your background and what you work on now?

I was born in a small town in India and first in my family to pursue science as a field of study and career. I did my bachelors in Microbiology from Madras Christian College, Chennai and my masters in Biotechnology from University of Hyderabad. I trained as a geneticist and molecular biologist during my years in PhD, but last year, I decided to leave the program to pursue my passion for science design and communication.

Were you always going to be a scientist?

Haha, or so I thought, but life had other plans. During my PhD, I discovered that while I loved reading, discussing, and visualising science, the hands-on research itself wasn’t where my true passion lay. Instead of feeling fulfilled, I often found myself more stressed than excited. Accepting this and choosing a different path wasn’t easy, but in hindsight, I’m grateful I did.

And what about art – have you always enjoyed it?

I have always loved art. While growing up I was the kind of kid who daydreamed in vivid colors, turned found objects into art, and saw potential in everything from leftover materials to doodles in the margins. In college, I have painted huge murals, designed T-shirts and logos, and participated in creative projects. Those days were filled with endless exploration, late night brainstorming sessions, and the thrill of bringing ideas to life.

What or who are your most important artistic influences?

I can’t think of a specific name, but my mother has been a major artistic influence throughout my life. She is incredibly creative and always encouraged me to explore and experiment with different artistic activities. Time during my bachelors degree was very inspiring for the creative in me. And Instagram, in particular, has been a great platform for inspiration lately.

How do you make your art?

I have had some fair share of experience with acrylics in the past, but in recent years, all my artworks are digital. I like to start with reading about the concept I will be working on. I like to get inspired from scientific data and microscopy
images. I initially started with Procreate on my iPad, and what an incredible experience that was! Eventually, I transitioned to more vector-based software like Adobe Illustrator. That said, I still rely on Procreate for rough sketches, storyboarding, and quick, fun artworks — it’s my go-to for spontaneous creativity.

Does your background in science influence your art?

Absolutely! Science is my playground to explore the weird and wonderful. If it wasn’t for science I don’t know if I would have gotten back to doing art. And I don’t see why I should restrict myself to just digital illustration. Science can be communicated in so many different visual art formats.

What are you thinking of working on next?

Since now this is what I do full time. My visual science communication agency, NERD, helps scientists, research institutes and biotech and healthcare companies communicate their science through various visual art formats and content creation. I have some interesting projects for this year and I am actively seeking for more exciting work. I’m currently working on a series, exploring the fascinating world of biomimicry through a unique digital content style, where we are highlighting 10 nature-inspired breakthroughs in science, tech, and sustainable design. This can be found on our Instagram and LinkedIn page.

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Humans and other tetrapods evolved from aquatic fish. In making this leap, tetrapods evolved lungs to breathe air and lost respiratory gills. It is tempting to intuit that lungs evolved from gills. However, lungs and gills form in separate parts of the body, so they are unlikely to be evolutionarily related. Indeed, some living fish have both gills and lungs [1]. So, what became of fish gills? In work spanning the last 6 years and published in Nature, we show that gills may in fact have contributed to the origin of a functionally unrelated structure in humans – our outer ears.

The outer ear, comprising the ear canal and flap-like pinna, is a unique feature of mammals with no known evolutionary precedent in reptiles or amphibians. At first, our research centered on the elastic cartilage that supports it, previously described only in mammals [2-5]. Elastic cartilage has cellular and mechanical properties distinct from the more widespread hyaline cartilage in the adult nose, joints, and embryonic skeleton. But we knew almost nothing about molecular drivers of these differences. In previous work in the Crump lab I had helped describe a zebrafish gill cartilage with gene expression distinct from hyaline cartilage. Ensuing discussions with Max Plikus at UC Irvine and a wonderful collaboration with Andrew Gillis at the MBL (in which he single-handedly sectioned and stained gills from multiple fish species!), helped established that cartilage in the gills of bony fishes, including zebrafish, is elastic in nature.

I next asked whether the elastic cartilage in fish gills and the mammalian outer ear might represent a homologous cell type. With help from the Evseenko lab at USC and cross-country shipments from collaborators in the Chen lab at Mount Sinai (once during a hurricane!), I acquired single-cell gene expression and open chromatin profiles from elastic cartilage of the human fetal outer ear and epiglottis, as well as hyaline cartilage from the human nose as a control and compared these with our zebrafish data. These analyses confirmed significant gene expression similarities between fish and human elastic cartilage.

At this point, two major conceptual ideas significantly expanded the focus of this work.

First, the activity of non-coding genomic elements called enhancers tends to be more tissue-specific than expression of associated genes, thus serving as better proxies for regulatory conservation between cell types. The problem is that unlike genes, only a tiny proportion of human enhancers have sequence-conserved counterparts in the zebrafish genome. However, previous work had shown that regulatory information encoded in enhancers can be recognized by similar sets of factors across species [6, 7]. This gave me the idea to sidestep the issue of DNA sequence conservation: if elastic cartilage is specified by a conserved regulatory program, then human elastic cartilage enhancers encoding this program might still be recognized specifically in fish gills.

I identified human genomic regions representing putative elastic cartilage-specific enhancers and, despite absence of similar fish sequences, tested their activity in zebrafish. It was the most incredible moment of my PhD when I looked through the microscope to see six of ten human outer ear elastic cartilage enhancers driving fluorescent activity specifically in the gills, reflecting shared biology across 400 million years of evolution. Equally amazing, a zebrafish gill elastic cartilage enhancer drove highly specific activity in the elastic cartilage of the mouse outer ear.

Second, I was influenced by work in other model systems showing that seemingly novel structures can represent re-emergence of an ancestral structure that apparently disappeared during evolution but was in fact retained in a cryptic form in intervening species [8]. Could a broader gill developmental circuitry have been retained in tetrapods and repurposed in mammals to drive outer ear evolution?

I realized we could use a similar enhancer-based approach, but with a focus on developmental timepoints when gills first grow out. This led to the discovery that one of the few enhancers well-conserved between zebrafish and humans is active in gill developmental populations, but critically not in the later-forming elastic cartilage. It thus represents a piece of the ancient instructions to make fish gills retained in our own DNA. In transgenic mice, the zebrafish version of this enhancer was faintly but consistently active in the developing outer ear. These findings demonstrated that it is not simply the elastic cartilage but also the early developmental outgrowth program that is evolutionarily conserved between fish gill filaments and the mammalian outer ear.

So, what was this program doing in amphibians and reptiles? In the case of our middle ear bones, fossil data have revealed their progressive evolution from fish jawbones through amphibian and reptile intermediates [9]. By contrast, cartilage does not preserve well, so the current fossil record provides little information on how gills may have transformed into outer ears.

For answers, we again turned to enhancers. We formed a new, eleventh-hour collaboration with Helen Willsey at UCSF to test our enhancers in an amphibian – the frog. Helen and her postdoc Micaela gave me a crash course on staging, imaging, and staining Xenopus tadpoles in the final weeks of my PhD, patiently repeating injections to replace samples that I lost. The results were worth it: gill/outer ear outgrowth enhancers were active in developing tadpole gills, suggesting continuity in the developmental program from fish to tetrapods. Further, mature tadpole gills contained a little-characterized cartilage that activated both human and zebrafish elastic cartilage enhancers! Although transgenic testing was not feasible in reptiles, I collaborated with Tom Lozito at USC to examine histology of the ear in green anole lizards and found that the evolutionarily mysterious extracolumella is made of a permanent, elastic cartilage. These pieces of evidence helped put together a model through which fish gill developmental and cell type programs could have been repeatedly redeployed through the evolution of tetrapods.

Finally, older reports had suggested that the horseshoe crab, an ancient invertebrate, makes a cellular type of cartilage-like tissue in its gills [10-13]. An exciting opportunity arose when I attended the wonderful Embryology Course held at the Marine Biological Laboratory (MBL), which happens to be in Atlantic horseshoe crab territory. From chats I had there with invertebrate evo-devo aficionado Heather Bruce (now at the University of British Columbia), I got in touch with the Marine Resource Center, acquired a horseshoe crab specimen, and performed single-nuclei multiomic analysis on its unique “book gills”. Amazingly, a horseshoe crab gill enhancer drove transgenic activity in the zebrafish gills! Although we can do only limited experimental work in horseshoe crabs, our data suggest that gills and their elastic cartilage support may have an ancient origin in early bilateria.

Traditionally, fish gills were thought to have played little role in the evolution of tetrapods. Now, our work reveals an unprecedent legacy for this complex ancestral structure. Our research supports the idea of “deep” or “cryptic” homology: the morphological disappearance of a structure does not imply the disappearance of the developmental field from which it emerged or the regulatory program that instructed its formation. These developmental fields and regulatory programs can instead be reused to make something new, contributing to the widespread innovation we observe in nature.

1.          Cupello, C., et al., Allometric growth in the extant coelacanth lung during ontogenetic development. Nature communications, 2015. 6(1): p. 8222.

2.          Sanzone, C.F. and E.J. Reith, The development of the elastic cartilage of the mouse pinna. American Journal of Anatomy, 1976. 146(1): p. 31-71.

3.          Bradamante, Z., B. Levak-Svajger, and A. Svajger, Differentiation of the secondary elastic cartilage in the external ear of the rat. The International journal of developmental biology, 1991. 35(3): p. 311-320.

4.         Cox, R. and M. Peacock, The fine structure of developing elastic cartilage. Journal of anatomy, 1977. 123(Pt 2): p. 283.

5.          Kostović-Knežević, L., Ž. Bradamante, and A. Švajger, Ultrastructure of elastic cartilage in the rat external ear. Cell and Tissue Research, 1981. 218: p. 149-160.

6.          Wong, E.S., et al., Deep conservation of the enhancer regulatory code in animals. Science, 2020. 370(6517): p. eaax8137.

7.          Minnoye, L., et al., Cross-species analysis of enhancer logic using deep learning. Genome research, 2020. 30(12): p. 1815-1834.

8.          Bruce, H.S. and N.H. Patel, The Daphnia carapace and other novel structures evolved via the cryptic persistence of serial homologs. Current Biology, 2022. 32(17): p. 3792-3799. e3.

9.          Gould, S.J., An earful of jaw. Natural History, 1990. 99(3): p. 12-18.

10.        Person, P. and D.E. Philpott, The biology of cartilage. I. Invertebrate cartilages: Limulus gill cartilage. Journal of Morphology, 1969. 128(1): p. 67-93.

11.         Person, P. and D.E. Philpott, Invertebrate cartilages. Annals of the New York Academy of Sciences, 1963. 109(1): p. 113-126.

12.         Cole, A.G. and B.K. Hall, The nature and significance of invertebrate cartilages revisited: distribution and histology of cartilage and cartilage-like tissues within the Metazoa. Zoology, 2004. 107(4): p. 261-273.

13.         Tarazona, O.A., et al., The genetic program for cartilage development has deep homology within Bilateria. Nature, 2016. 533(7601): p. 86-89.

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Applications to the new Master in Integrative Biological Sciences (iBioS) are opened

Dear student,

You are currently finishing, or already have, a Bachelor’s degree in Biological Sciences? You are highly motivated, and you are looking for an innovative, immersive and truly international master program? Then, iBioS is what you are searching for!

This immersive research-driven training program will train high-level international students in all areas of research developed in our ITI IMCBio+ with a strong emphasis on hands-on experience as well as innovation via internships and tutored projects. Training will be fully in English.

In a nutshell, iBioS (integrative Biological Sciences) is an advanced training to research through research that will offer you:

– A training fully in English

– A unique mentoring program in which each student will benefit from privileged interactions with 2 renown scientists that will provide personalized guidance and support all along the two years of training

– A personalized training. Each student will select a set of courses offered by the faculty of life sciences and that he/she thinks matches best his/her expectations and needs. Here again, the student will benefit from the guidance of his/her mentors right from the beginning of the program.

– 10 months of internship in labs belonging to 5 worldwide renown research institutes in which you will access the latest technologies and advanced facilities.

– A unique immersive tutored project spanning the three first semesters of the master. This group work will bring you to design a scientific project through literature survey. Your creativity will also be strongly stimulated since you will have to design and budget a set of experiments that the IMCBio graduate school will finance to enable you to put them in practice under the guidance of experts. Finally, you will be trained to exploit the produced data by writing a scientific publication and presenting your achievements in a conference.

– A training in intellectual property provided through dedicated courses, but also a workshop supervised by our technological transfer office and meetings with entrepreneurs and investors.

– A set of courses in biocomputing and ethics and other activities customized for this program.

How to apply?

You are excited by this program and you want to challenge yourself? So don’t hesitate anymore: apply on MonMaster (https://monmaster.gouv.fr/formation/0673021V/1800705SXQ4J/detail) before March 24th.

More information on IMCBio website (https://imcbio.unistra.fr/imcbio-training-programs/#master)

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The island of Capri, lying south of Naples and West of Sorrento, is an Italian vacation destination known for its exquisite views and extravagant luxury shopping. So, it may come as a surprise to think that this could also be an ideal location where science-based education on human brain development might occur. Well, for one week in October 2024, this was indeed the case as the European Molecular Biology Organization (EMBO) hosted a workshop titled “Unlocking human brain complexity using 3D culture and single cell omics.”

EMBO workshops are typically smaller conferences, with an attendance size of about 100 or so registrants, to provide a more intimate atmosphere that promotes close interaction among scientists. The exotic setting of the host site also offers a more relaxed environment to foster networking and encourage collaborative discussions between research groups.

This EMBO workshop in Capri did not disappoint, and it served as a “Who’s Who” in the cerebral organoid research field, touting a roster of distinguished speakers highlighted by Sergiu Pasca, Madeline Lancaster, Jurgen Knoblich, Barbara Treutlein, and Paola Arlotta — a Mount Rushmore worthy collection of scientists in the in vitro stem cell brain development field. 

The workshop started off with a bang, led by a plenary lecture from Paola Arlotta, Ph.D., Professor and Chair of Harvard University’s Department of Stem Cell & Regenerative Biology (HSCRB), who detailed her lab’s work on the use of multi-donor stem cell villages to generate chimeric organoids to investigate population-wide differences in brain development and susceptibility to disease-causing environmental agents https://www.nature.com/articles/s41586-024-07578-8.

Later, we heard from Barbara Treutlein, Ph.D., Principal Investigator at ETH Zurich, on her lab’s use of multi-omics platforms and computational analysis pipeline to study human brain development. Recently, her team and others in the field have collaborated to compile transcriptomic datasets from neural organoid protocols while cross-referencing against existing brain atlases to generate an integrated organoid cell atlas https://www.nature.com/articles/s41586-024-08172-8.

On the topic of neural organoids, we heard from Jurgen Knoblich, Ph.D., Professor of Synthetic Biology at the Medical University of Vienna and Scientific Director at IMBA, who presented a set of new protocols to generate diverse neural subtypes https://www.biorxiv.org/content/10.1101/2024.11.15.623576v1. Meanwhile, Madeline Lancaster, Ph.D., Professor at MRC Laboratory of Molecular Biology (UK), discussed the challenges with organoid reproducibility across biologically diverse human induced pluripotent stem cell lines (hiPSCs). 

Another interesting theme that came from the meeting was the dynamic use of growth factor morphogen signals, known to construct the developing nervous system, in these in vitro derived organoid models. Additional work from the Treutlein lab has used morphogenetic analysis using high content imaging https://www.biorxiv.org/content/10.1101/2023.08.21.553827v1, along with multiplexed omics assays https://www.biorxiv.org/content/10.1101/2024.02.08.579413v1, to profile this dynamic range of morphogen signaling that is both time and concentration dependent; as have others https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00378-3.

Additionally, we heard from different groups detailing the versatility of specific morphogens, such as FGF8, in patterning diverse regions of the brain from anterior-derived pallial subtypes https://elifesciences.org/articles/98096 to posterior-defined hindbrain derivatives like cerebellum https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00430-7.

Finally, not to be overshadowed, was the incredible (and futuristic) work from the lab of Sergiu Pasca, MD., Professor of Psychiatry and Director of the Stanford Brain Organogenesis program. Sergiu’s lab is arguably revolutionizing the stem cell field with his team’s pioneering work on organoid assemblies, coined ‘assembloids’ https://www.nature.com/articles/d41586-021-02628-x. Most recently, his lab has generated diverse assembloid models to recreate intricate connections between regional boundaries of the developing neural tube https://www.biorxiv.org/content/10.1101/2024.06.26.600229v1, ascending pathways in the CNS https://www.biorxiv.org/content/10.1101/2024.03.11.584539v1, and modeling unique circuits within the brain https://www.biorxiv.org/content/10.1101/2024.10.13.617729v1.

While you might think that all this fascinating science was the highlight of the conference, there were also several amazing extracurricular events such as free-periods to explore the island, evening dinners with the expert speakers, and a conference-ending gala featuring folk dancers, singers, and musicians playing traditional Neapolitan music.

So, the next time you find yourself vacationing on an island, either in Capri or elsewhere, imagine that a group of scientists could be congregating nearby to discuss the latest scientific discoveries on the development of our human brains.

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As well as looking for the next Executive Editor for Development, we are also recruiting a Reviews Editor on the journal. If you love developmental biology but don’t want to be ‘doing’ it any more, this is a great opportunity to stay connected to the field and the community and to help shape the content of the journal. You’ll commission and edit review-type articles and perspectives, conduct interviews, write research highlights, travel to conferences and contribute to the strategic development of the journal. As a small publishing company, you’ll get great exposure to all aspects of the business – both the publishing and the charitable side – and you’ll also get to work for an organisation that really believes in supporting the academic community. All the details can be found in the job advert on our website.

You don’t need to have prior editorial experience (though obviously we’d be delighted to receive applications from people who do); what you do need are research experience and a broad interest in the field, excellent communication skills, and a willingness to learn! If this sounds like something you might be interested in, please feel free to get in touch with informal questions, or just apply directly (instructions in the job ad). The deadline for applications is 31 March 2025.

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Welcome to our monthly trawl for developmental and stem cell biology (and related) preprints.

The preprints this month are hosted on bioRxiv – use these links below to get to the section you want:

Developmental biology

• Patterning & signalling
• Morphogenesis & mechanics
• Genes & genomes
• Stem cells, regeneration & disease modelling
• Plant development
• Environment, evolution and development

Cell Biology

Modelling

Tools & Resources

Developmental biology

| Patterning & signalling

Mac/Lac-tosylceramide regulates intestinal homeostasis and secretory cell fate commitment by facilitating Notch signaling

Kebei Tang, Xuewen Li, Jiulong Hu, Jingyuan Shi, Yumei Li, Yansu Chen, Chang Yin, Fengchao Wang, Rongwen Xi

Genetic evidence: zebrafish hoxba and hoxbb clusters are essential for the anterior-posterior positioning of pectoral fins

Morimichi Kikuchi, Renka Fujii, Daiki Kobayashi, Yuki Kawabe, Haruna Kanno, Sohju Toyama, Farah Tawakkal, Kazuya Yamada, Akinori Kawamura

Geometry-driven asymmetric cell divisions pattern cell cycles and zygotic genome activation in the zebrafish embryo

Nikhil Mishra, Yuting I. Li, Edouard Hannezo, Carl-Philipp Heisenberg

Insect wings arose with a genetic circuit that extends the useful range of a BMP morphogen

Anqi Huang, Luca Cocconi, Ben Nicholls-Mindlin, Cyrille Alexandre, Guillaume Salbreux, Jean-Paul Vincent

Divergent Hox cluster collinearity in horned beetles reveals adult head patterning function of labial

Erica M. Nadolski, Isabel G. Manley, Sukhmani Gill, Armin P. Moczek

Geometric, cell cycle and maternal-to-zygotic transition-associated YAP dynamics during preimplantation embryo development

Madeleine Chalifoux, Maria Avdeeva, Eszter Posfai

Measuring morphogen transport over multiple spatial scales in live zebrafish embryos

Ashwin V. S. Nelanuthala, Bitan Saha, Jagadish Sankaran, Tom J. Carney, Karuna Sampath, Thorsten Wohland

Anti-resonance in developmental signaling regulates cell fate decisions

Samuel J. Rosen, Olivier Witteveen, Naomi Baxter, Ryan S. Lach, Marianne Bauer, Maxwell Z. Wilson

CHD3 regulates BMP signalling response during cranial neural crest cell specification

Zoe H. Mitchell, Joery den Hoed, Willemijn Claassen, Martina Demurtas, Laura Deelen, Philippe M. Campeau, Karen Liu, Simon E. Fisher, Marco Trizzino

Shared Lineage, Distinct Outcomes: Yap and Taz Loss Differentially Impact Schwann and Olfactory Ensheathing Cell Development Without Disrupting GnRH-1 Migration

Ed Zandro M. Taroc, Enrico Amato Jr., Alexis Semon, Nikki Dolphin, Briane Beck, Sophie Belin, Yannick Poitelon, Paolo E. Forni

Bdnf-Ntrk2 Signaling Promotes but is not Essential for Spinal Cord Myelination in Larval Zebrafish

Kristen Russell, Christina A. Kearns, Macie B. Walker, Christopher S. Knoeckel, Angeles B. Ribera, Caleb A. Doll, Bruce Appel

| Morphogenesis & mechanics

Endoderm differentiates into a transient epidermis in the mouse perineum

Christine E. Larkins, Daniel M. Grunberg, Gabriel M. Daniels, Erik J. Feldtmann, Martin J. Cohn

Molecular insights into electroreceptor ribbon synapses from differential gene expression in sturgeon lateral line organs

Alexander S. Campbell, Martin Minařík, David Buckley, Tanmay Anand, David Gela, Martin Pšenička, Clare V. H. Baker

Myelination across cortical hierarchies and depths in humans and macaques

Monami Nishio, Xingyu Liu, Allyson P. Mackey, Michael J. Arcaro

Defects in nephrogenesis result in an expansion of the Foxd1+ stromal progenitor population

Michael G. Michalopulos, Yan Liu, Dinesh Ravindra Raju, John T. Lafin, Yanru Ma, Dhruv Gaur, Sadiksha Khadka, Chao Xing, Andrew P. McMahon, Thomas J. Carroll, Keri A. Drake

Analysis of molecular and cellular bases of honey bee mushroom body development

Shuichi Kamata, Takeo Kubo, Hiroki Kohno

Cross-Species Biomechanical Determinants of Shape Diversity

Richard Bailleul, Nicolas Cuny, Diana Khoromoskaia, Soham Basu, Giulia Bergamini, Paolo Cucurachi, Sebastian Rupp, Annika Guse, Camille Curantz, Natalie Swinhoe, Phillip Cleves, Jamie Craggs, Sosuke Fujita, Yu-ichiro Nakajima, Petrus J. Steenbergen, Alba Diz-Muñoz, Guillaume Salbreux, Aissam Ikmi

Testosterone exposure during fetal masculinization programming window determines the kidney size in adult mice

Arttu Junnila, Kalle T. Rytkönen, Guillermo Martinez-Nieto, Mats Perk, Hao Li, Jenni Airaksinen, Ida Hyötyläinen, Oliver Mehtovuori, Asta Laiho, Claes Ohlsson, Laura L. Elo, Satu Kuure, Matti Poutanen, Petra Sipilä

Mouse scalp development requires Rac1 and SRF for the maintenance of mechanosensing mesenchyme

Bharath H. Rathnakar, Alex Rackley, Hae Ryong Kwon, William L. Berry, Lorin E. Olson

A prevalent Krt8-to-Krt5 cellular state transition in skin is co-opted by p63 for enamel organ development

Qinghuang Tang, Jung-Mi Lee, Liwen Li, Chunmiao Cai, Hunmin Jung, Hyuk-Jae Edward Kwon

Development of the zebrafish anterior lateral line system is influenced by underlying cranial neural crest

Vishruth Venkataraman, Noel H. McGrory, Theresa J. Christiansen, Joaquin Navajas Acedo, Michael I. Coates, Victoria E. Prince

Additive effects on craniofacial development upon conditional ablation of PDGFRα and SHP2 in the mouse neural crest lineage

Daniel Fuhr, Jessica Johnston, Elliott P. Brooks, Katherine A. Fantauzzo

Keratins coordinate tissue spreading by balancing spreading forces with tissue material properties

Suyash Naik, Yann-Edwin Keta, Kornelija Pranjic-Ferscha, Édouard Hannezo, Silke Henkes, Carl-Philipp Heisenberg

mTOR regulates Wnt signaling to promote tension-mediated lens vesicle closure

Qian Wang, Hao Wu, Yingyu Mao, Alyssa Chow, Michael Bouaziz, Yihua Wu, Xin Zhang

A myofilament lattice model of Drosophila flight muscle sarcomeres based on multiscale morphometric analysis during development

Péter Görög, Tibor Novák, Tamás F. Polgár, Péter Bíró, Adél Gutheil, Csaba Kozma, Tamás Gajdos, Krisztina Tóth, Alexandra Tóth, Miklós Erdélyi, József Mihály, Szilárd Szikora

Altered pseudostratified epithelial development of the lateral ventricle choroid plexus in Mllt11 mutants

Sam Moore, Danielle Stanton-Turcotte, Angelo Iulianella

Noncanonical Wnt/Ror2 Signaling Regulates Basal Cell Fidelity and Branching Morphogenesis in the Mammary Gland

Hongjiang Si, Erika Mendoza Mendoza, Madelyn Esquivel, Chad J. Creighton, Jianming Xu, Kevin Roarty

| Genes & genomes

Active DNA demethylation is upstream of rod-photoreceptor fate determination and required for retinal development

Ismael Hernández-Núñez, Alaina Urman, Xiaodong Zhang, William Jacobs, Christy Hoffman, Sohini Rebba, Ellen G Harding, Qiang Li, Fengbiao Mao, Andi K Cani, Shiming Chen, Meelad M Dawlaty, Rajesh C Rao, Philip A Ruzycki, John R Edwards, Brian S Clark

Mismatch repair and homologous recombination are yin-yang partners in hybrid zygote meiosis

Chi-Ning Chuang, Ya-Ling Hung, Hong-Xiang Kim, Jhong-Syuan Yao, Hou-Cheng Liu, Sheng-Yuan Chen, Lavernchy Jovanska, Yi-Ping Hsueh, Ruey-Shyang Chen, Ting-Fang Wang

Spatially regulated mRNA decay sharpens expression patterns in the Drosophila embryo

Jennifer C. Love, Lauren Forbes Beadle, Catherine Sutcliffe, Magnus Rattray, Hilary L. Ashe

Differential Roles of Broadly Expressed Transcription Factors in Early Cardiac Cell Specification

Shiva Abbasi, Evangelia Chrysostomou, Georgios Tegousis, Oscar Villasana Espinosa, Rie Conley, Theodora Koromila

MYRF is Essential in Mesothelial Cells to Promote Lung Development and Maturation

Gidsela Luna, Jamie Verheyden, Chunting Tan, Estelle Kim, Michelle Hwa, Jugraj Sahi, Yufeng Shen, Wendy Chung, David McCulley, Xin Sun

Feed-forward loops by NR5A2 ensure robust gene activation during pre-implantation development

Wataru Kobayashi, Siwat Ruangroengkulrith, Eda Nur Arslantas, Adarsh Mohanan, Kikue Tachibana

The mex-3 3’ untranslated region is essential for reproduction during temperature stress

Hannah E. Brown, Haik V. Varderesian, Sara A. Keane, Sean P. Ryder

Dora, a key component of target-directed miRNA degradation, is essential for local genomic amplification in Drosophila ovarian follicle cells

Natalia Akulenko, Oxana Olenkina, Elena Mikhaleva, Sofya Marfina, Anastasia Krylova, Stepan Toshchakov, Sergei Ryazansky

Single-Cell Roadmap of Early Hemato-Endothelial Development: Functions of Atf3, Zfp711 and Bcl6b

Ridvan Cetin, Giulia Picco, Jente van Staalduinen, Eric Bindels, Remco Hoogenboezem, Gregory van Beek, Mathijs A Sanders, Yaren Fidan, Ahmet Korkmaz, Joost Gribnau, Jeffrey van Haren, Danny Huylebroeck, Eskeatnaf Mulugeta, Frank Grosveld

Single-nucleus multiomics of murine gonadal cells reveals transcriptional regulatory network underlying supporting lineage differentiation

Yu-Ying Chen, Karina Rodriguez, Adriana K. Alexander, Xin Xu, Brian Papas, Martin A. Estermann, Humphrey Hung-Chang Yao

Lysine-specific demethylase 1a is obligatory for gene regulation during kidney development

Savithri Balasubramanian Kota, Satya K. Kota

| Stem cells, regeneration & disease modelling

Dependence of cell fate potential and cadherin switching on primitive streak coordinate during differentiation of human pluripotent stem cells

Ye Zhu, Aryeh Warmflash

A kinetics-based model of hematopoiesis reveals extrinsic regulation of skewed lineage output from stem cells

Esther Rodríguez-Correa, Florian Grünschläger, Tamar Nizharadze, Natasha Anstee, Jude Al-Sabah, Vojtech Kumpost, Anastasia Sedlmeier, Congxin Li, Melanie Ball, Foteini Fotopoulou, Jeyan Jayarajan, Ian Ghezzi, Julia Knoch, Megan Druce, Theo Aurich, Marleen Büchler-Schäff, Susanne Lux, Pablo Hernández-Malmierca, Julius Gräsel, Dominik Vonficht, Anna Mathioudaki, Judith Zaugg, Ralf Mikut, Andreas Trumpp, Thomas Höfer, Daniel Hübschmann, Simon Haas, Michael D. Milsom

Chronic alcohol consumption enhances the differentiation capacity of hematopoietic stem and progenitor cells into osteoclast precursors

Hami Hemati, Madison B. Blanton, Jude koura, Rupak Khadka, Kathleen A. Grant, Ilhem Messaoud

Dimethyl sulfoxide primes induced pluripotent stem cells for more efficient nephron progenitor and kidney organoid differentiation

Helen Kearney, Aleksandra Rak-Raszewska, Adrián Seijas-Gamardo, Enrique Escarda-Castro, Paul Wieringa, Lorenzo Moroni, Carlos Mota

Quiescence modulates age-related changes in the functional capacity of highly proliferative canine lung mesenchymal stromal cell populations

Nakesha Agyapong, Leslie Dominguez-Ortega, Brian Macdonough, Patrick Mulluso, Sagar Patel, Briti Prajapati, Brian Saville, Andrew Shapiro, Ethan Trim, Kara Battaglia, Jocelyn Herrera, Gianna Garifo-MacPartland, Dianne Newcombe, Latoya Okundaye, Heather Paglia, Julia Paxson

Senolytics restore hematopoietic stem cell function in sickle cell disease

Aditya Barve, Adam Cornwell, Pramika Sriram, Alex Kopyov, Preeti Dabas, Emilia Kooienga, Zakiya Kelley, James Johnson, Jacquelyn A. Myers, Esther A. Obeng, Guolian Kang, Yunus Olufadi, Terri Cain, Lindsay Talbot, David Spence, Mauricio Cortes, Sam Miller, Dirk Loeffler, Akshay Sharma, Shannon McKinney-Freeman

Human pluripotent stem cell-derived intestinal epithelial cells maintain small intestine-specific functions over time, even with repeated cell division

Junlong Chen, So Kuramochi, Shinichiro Horiuchi, Tomoyuki Kawasaki, Hiroto Kakizaki, Lirika Tabata, Tohru Kimura, Kazuaki Nakamura, Hidenori Akutsu, Seiichi Ishida, Akihiro Umezawa

Canonical Hedgehog Signaling Controls Astral Microtubules and Mitotic Spindle Orientation in Neural Progenitors and iPSCs

Fengming Liu, Anna Medyukhina, Kris M Olesen, Abbas Shirinifard, Hongjian Jin, Lei Li, Marina Mapelli, Khaled Khairy, Young-Goo Han

YY1 protein is essential for the promotion of Muller glia reprogramming and retina regeneration

Mansi Chaudhary, Omkar Mahadeo Desai, Poonam Sharma, Sharanya Premraj, Pooja Shukla, Rajesh Ramachandran

Analysis of The Senescence Secretome During Zebrafish Retina Regeneration

Gregory J. Konar, Kyle T. Vallone, Tu D. Nguyen, James G. Patton

Platelet endocytosis and α-granule cargo packaging are essential for normal skin wound healing

Daniëlle M. Coenen, Hammodah R. Alfar, Sidney W. Whiteheart

Cooperation between proximate cell layers drives large-scale wound closure prior to whole-body regeneration

Allison P. Kann, Mansi Srivastava

Ectopic head regeneration after nervous system ablation in a sea anemone

Fatemeh Mazloumi Gavgani, Johanna E.M. Kraus, Joshua November, Layla Al-Shaer, Anna Cosima Seybold, Benjamin Lerstad, Harald Hausen, Michael J. Layden, Fabian Rentzsch

Divergent stem cell mechanisms governing the primary body axis and appendage regeneration in the axolotl

Liqun Wang, Li Song, Chao Yi, Jing Zhou, Zhouying Yong, Yan Hu, Xiangyu Pan, Na Qiao, Hao Cai, Wandong Zhao, Rui Zhang, Lieke Yang, Lei Liu, Guangdun Peng, Elly M Tanaka, Hanbo Li, Yanmei Liu, Ji-Feng Fei

Specific cell states underlie complex tissue regeneration in spiny mice

Emilio Oviedo Rivadeneira, Robyn Allen, Mike Adam, Ashley W. Seifert

A Single Mutation in TRPC6 Protects Mice from Acute Lung Injury by Regenerating Endothelium

Mumtaz Anwar, Vijay Avin Balaji Raghunathrao, Ruhul Amin, Vigneshwaran Vellingiri, Jagdish Chandra Joshi, Md Zahid Akhter, Mohammad Tauseef, Ibrahim Hassan El-Erian, Nazanin Khaki, Ibra S. Fancher, Hazem Abdelkarim, Irena Levitan, Konstantinos Chronis, Vadim Gaponenko, Dolly Mehta

Cloche/Npas4l is a pro-regenerative platelet factor during zebrafish heart regeneration

Junjie Hou, Yabing Song, Chenglu Xiao, Yuanyuan Sun, Jie Shen, Xiaokai Ma, Qinchao Zhou, Shih-Ching Chiu, Yang Xu, Yanyi Huang, Ye-Guang Chen, Xiaojun Zhu, Jianbin Wang, Jing-Wei Xiong

ZEB2 signaling is essential for ureteral smooth muscle cell differentiation and maintenance

Sudhir Kumar, Xueping Fan, Harshita Pattam, Kun Yan, Easton Jinhun Liaw, Jiayi Ji, Emily Zaltz, Paul Song, Yuqiao Jiang, Yuriko Nishizaki, Yujiro Higashi, Chen-Leng Cai, Weining Lu

Intersecting impact of CAG repeat and Huntingtin knockout in stem cell-derived cortical neurons

Jennifer T. Stocksdale, Matthew J. Leventhal, Stephanie Lam, Yu-Xin Xu, Yang Oliver Wang, Keona Q. Wang, Reuben Tomas, Zohreh Faghihmonzavi, Yogi Raghav, Charlene Smith, Jie Wu, Ricardo Miramontes, Kanchan Sarda, Heather Johnson, Min-Gyoung Shin, Terry Huang, Mikelle Foster, Mariya Barch, Naufa Armani, Chris Paiz, Lindsay Easter, Erse Duderstadt, Vineet Vaibhav, Niveda Sundararaman, Dan P. Felsenfeld, Thomas F. Vogt, Jennifer Van Eyk, Steve Finkbeiner, Julia A. Kaye, Ernest Fraenkel, Leslie M. Thompson

A cell-type specific surveillance complex represses cryptic promoters during differentiation in an adult stem cell lineage

Neuza R. Matias, Lorenzo Gallicchio, Dan Lu, Jongmin J. Kim, Julian Perez, Angela M. Detweiler, Chenggang Lu, Benjamin Bolival, Margaret T. Fuller

An increase in reactive oxygen species underlies neonatal cerebellum repair

Anna Pakula, Salsabiel El Nagar, N. Sumru Bayin, Jens Bager Christensen, Daniel N. Stephen, Adam James Reid, Richard Koche, Alexandra L. Joyner

Hematopoietic stem cells undergo bidirectional fate transitions in vivo

Tsuyoshi Fukushima, Trine Ahn Kristiansen, Lai Ping Wong, Samuel Keyes, Yosuke Tanaka, Michael Mazzola, Ting Zhao, Lingli He, Masaki Yagi, Konrad Hochedlinger, Satoshi Yamazaki, Ruslan I. Sadreyev, David T Scadden

Muscle stem cell activation in response to acute injury is promoted by transient exposure to neutrophil elastase

Christopher J. Clarke, Amy Stonadge, Ethan Aminov, Addolorata Pisconti

| Plant development

Regulation of early-stage tomato fruit growth by the splicing factor RS2Z36

Stavros Vraggalas, Remus RE Rosenkranz, Mario Keller, Yolanda Pérez-Pérez, Samia Bachiri, Kerstin J Zehl, Jessica Bold, Stefan Simm, Arindam Ghatak, Wolfram Weckwerth, Leila Afjehi-Sadat, Palak Chaturvedi, Pilar S Testillano, Michaela Müller-McNicoll, Kathi Zarnack, Sotirios Fragkostefanakis

Multiple fertility restorer loci for cytoplasmic male sterility caused by orf137 in tomato

Yurie Iki, Issei Harada, Kentaro Ezura, Seira Mashita, Kosuke Kuwabara, Hitomi Takei, Atsushi Toyoda, Kenta Shirasawa, Tohru Ariizumi

Shoot at Site: Advancing in planta transformation, regeneration and gene-editing through a cascade of wounding-mediated developmental regulators

Arjun Ojha Kshetry, Kaushik Ghose, Anshu Alok, Vikas Devkar, Vidhyavathi Raman, Robert M. Stupar, Luis Herrera-Estrella, Feng Zhang, Gunvant B. Patil

Transcriptomic insights into the role of miR394 in the regulation of flowering time in Arabidopsis thaliana

Federico Belen, Yanel Bernardi, Andrea Reutemann, Abelardo Vegetti, Marcela Dotto

Protein and genetic interactions between RACK1A and FSD1 modulate plant development and stress granule-dependent response to salt in Arabidopsis

Pavol Melicher, Petr Dvořák, Maryna Tsinyk, Jan Řehák, Olga Šamajová, Kateřina Hlaváčková, Miroslav Ovečka, Jozef Šamaj, Tomáš Takáč

The ribosomal protein RPS6A modulates auxin signalling and root development in Arabidopsis

Kai Pan, Kai Hou, Mengjuan Kong, Shutang Tan

Spatial and single-cell expression analyses reveal complex expression domains in early wheat spike development

Xiaosa Xu, Huiqiong Lin, Junli Zhang, German Burguener, Francine Paraiso, Connor Tumelty, Chengxia Li, Yuchen Liu, Jorge Dubcovsky

| Environment, evolution and development

Physical disturbance induces heart stop in mangrove killifish, Kryptolebias marmoratus embryos

Rosalie Herbert, Alexander David Corbett, Tetsuhiro Kudoh

Evolution of developmental bias explains divergent patterns of phenotypic evolution

Joao Picao-Osorio, Charlotte Bouleau, Pablo M. Gonzalez de la Rosa, Lewis Stevens, Nina Fekonja, Mark Blaxter, Christian Braendle, Marie-Anne Félix

Comparative genomics of sex determination related genes reveals shared evolutionary patterns between bivalves and mammals, but not Drosophila

Filippo Nicolini, Sergey Nuzhdin, Fabrizio Ghiselli, Andrea Luchetti, Liliana Milani

Genetic parallels in biomineralization of the calcareous sponge Sycon ciliatum and stony corals

Oliver Voigt, Magdalena V. Wilde, Thomas Fröhlich, Benedetta Fradusco, Sergio Vargas, Gert Wörheide

NSAID-mediated cyclooxygenase inhibition disrupts ectodermal derivative formation in axolotl embryos

Emma J. Marshall, Raneesh Ramarapu, Tess A. Leathers, Nikolas Morrison-Welch, Kathryn Sandberg, Maxim Kawashima, Crystal D. Rogers

Tooth development in frogs: Implications for the re-evolution of lost mandibular teeth and the origin of a morphological innovation

Daniel J Paluh, Madeline Brinkman, Kyliah Gilliam-Beale, Daniela Salcedo-Recio, Jacob Szafranski, James Hanken, Gareth J Fraser

Shaping of developmental gradients through selection on multiple loci in Antirrhinum

Desmond Bradley, Louis Boell, Daniel Richardson, Lucy Copsey, Annabel Whibley, Ting Xu, Yue Zhang, Yongbiao Xue, David Field, Enrico Coen

Antero-posterior patterning in the brittle star Amphipholis squamata and the evolution of body plans across echinoderms

L. Formery, P. Peluso, D. R. Rank, D. S. Rokhsar, C. J. Lowe

Parallel adaptation to geothermally-warmed habitats due to common structural variation and functional developmental pathways

Matthew K. Brachmann, Ana P. B. Costa, Shaun Robertson, Kate Donoghue, Natalie Pilakouta, Mark Whitehead, Xuan Liu, Bjarni Kristjansson, Skuli Skulason, Colin Selman, Kevin Parsons

Perinatal Nicotine Exposure Disrupts Hematopoietic Stem Cell Development and Elevates Influenza Susceptibility in Adulthood

T Cool, A Rodriguez y Baena, MGE Rommel, C Mattingly, E Bachinsky, S Saini, S Chattopadhyaya, BA Manso, S Rajendiran, AK Worthington, DM Poscablo, A Deguzman, T Berger-Cahn, DF Boyd, EC Forsberg

Enteric neural crest development in Astyanax mexicanus surface fish and cavefish

Pavani Ponnimbaduge Perera, Kaitlyn Webster, Misty R Riddle

Six million years of vole dental evolution driven by tooth development

Fabien Lafuma, Élodie Renvoisé, Julien Clavel, Ian J. Corfe, Gilles Escarguel

Cell Biology

Dysregulation of cell migration by matrix metalloproteinases in geleophysic dysplasia

Alejo A. Morales, Vladimir Camarena, LéShon Peart, Sarah Smithson, Lindsay Shaw, Lucy Webber, Jose M. Negron, Juan E. Sola, Ann-Christina Brady, Katherina Walz, Gaofeng Wang, Mustafa Tekin

Mitophagy at the oocyte-to-zygote transition promotes species immortality

Siddharthan Balachandar Thendral, Sasha Bacot, Katherine S. Morton, Qiuyi Chi, Isabel W. Kenny-Ganzert, Joel N. Meyer, David R. Sherwood

Treatment of human oocytes with extracellular vesicles from follicular fluid during rescue in vitro maturation enhances maturation rates and modulates oocyte proteome and ultrastructure

Sofia Makieva, Mara D. Saenz-de-Juano, Carmen Almiñana, Stefan Bauersachs, Sandra Bernal-Ulloa, Min Xie, Ana G. Velasco, Natalia Cervantes, Maike Sachs, Susanne E. Ulbrich, Brigitte Leeners

Polarity reversal of stable microtubules during neuronal development

Malina K. Iwanski, Albert K. Serweta, H. Noor Verwei, Bronte C. Donders, Lukas C. Kapitein

Super-resolution compatible DNA labeling technique reveals chromatin mobility and organization changes during differentiation

Maruthi K. Pabba, Miroslav Kuba, Tomáš Kraus, Kerem Celikay, Janis Meyer, Sunik Kumar Pradhan, Andreas Maiser, Hartmann Harz, Heinrich Leonhardt, Karl Rohr, Michal Hocek, M. Cristina Cardoso

Drosophila embryo cellularization is modulated by the viscoelastic dynamics of cortical-membrane interactions

Kyle Stark, Mayte Bonilla Quintana, Anna Marie Sokac, Padmini Rangamani

Drosophila larval gut transcriptome reveals a microbe-mediated intestinal tissue growth via Ecdysone during adaptive growth

Longwei Bai, Stéphanie Bellemin, Coralie Drelon, Pauline Joncour, Elodie Guillemot, Maura Strigini, Benjamin Gillet, François Leulier, Cathy Isaura Ramos

Remodeling of extracellular matrix collagen IV by MIG-6/papilin regulates neuronal architecture

Malika Nadour, Robert I. Valette Reveno Leatis, Marie Biard, Noémie Frébault, Lise Rivollet, Philippe St-Louis, Cassandra R. Blanchette, Andrea Thackeray, Paola Perrat, Carlo Bevilacqua, Robert Prevedel, Laurent Cappadocia, Georgia Rapti, Maria Doitsidou, Claire Y. Bénard

Prolonged metaphase II arrest weakens Aurora B/C- dependent error correction in mouse oocytes

Antoine Langeoire, Alison Kem-Seng, Damien Cladière, Katja Wassmann, Eulalie Buffin

Mammalian oocytes receive maternal-effect RNAs from granulosa cells

Caroline A. Doherty, Abdulfatai Tijjani, Steven C. Munger, Diana J. Laird

Molecular organization of the distal tip of vertebrate motile cilia

Juyeon Hong, Chanjae Lee, Ophelia Papoulas, Jiehong Pan, Maki Takagishi, Nadia Manzi, Daniel Dickinson, Amjad Horani, Steven Brody, Edward Marcotte, Tae Joo Park, John B Wallingford

Cell-penetrating peptide-mediated mouse oocyte activation

Toru Suzuki

Rapid pronucleus assembly using cytoplasmic RNAs in fertilized eggs of Xenopus laevis

Mizuki Ikeda, Yuto Tanaka, Tatsuya Shohoji, Yuki Hara

A Critical Role for the Fascin Family of Actin Bundling Proteins in Axon Development, Brain Wiring and Function

Katherine R. Hardin, Arjolyn B. Penas, Shuristeen Joubert, Changtian Ye, Kenneth R. Myers, James Q. Zheng

Dysregulation of the actin cytoskeleton and FMRP causes polar body protrusion defects in human fragile X premutation and aged oocytes

Kelly McCarter, Madhura Deshpande, Phillip Romanski, Christina Anna Stratopoulou, Nikica Zaninovic, Momina Tareen, Razan Al-Mousawi, Daylon James, Advaitha Madireddy, Zev Rosenwaks, Jeannine Gerhardt

NOR1 and Mitophagy: An Insight into Sertoli Cell Function Regulating Spermatogenesis

Bhola Shankar Pradhan, Deepyaman Das, Hironmoy Sarkar, Indrashis Bhattacharya, Subeer S Majumdar

In toto imaging of germ plasm dynamics reveals an essential role for early distribution of germ granules in germline development

Andreas Zaucker, Maria Papafoti, David Corcoran, DaeNia La Shawn La Rodé, Rebecca Leech, Pavle Vrliczak, Pooja Kumari, Karuna Sampath

Modelling

Predicting organoid morphology through a phase field model: insights into cell division and lumenal pressure

Sakurako Tanida, Kana Fuji, Linjie Lu, Tristan Guyomar, Byung Ho Lee, Alf Honigmann, Anne Grapin-Botton, Daniel Riveline, Tetsuya Hiraiwa, Makiko Nonomura, Masaki Sano

Modeling Epithelial Morphogenesis and Cell Rearrangement during Zebrafish Epiboly: Tissue Deformation, Cell-Cell Coupling, and the Mechanical Response to Stress

Sharon B. Minsuk, T. J. Sego, David M. Umulis, Mary C. Mullins, James A. Glazier

Generative model for the first cell fate bifurcation in mammalian development

Maria Avdeeva, Madeleine Chalifoux, Bradley Joyce, Stanislav Y. Shvartsman, Eszter Posfai

Mathematical modelling predicts novel mechanisms of stream confinement from Trail/Colec12/Dan in the collective migration of cranial neural crest cells

Samuel W.S. Johnson, Paul M. Kulesa, Ruth E. Baker, Philip K. Maini

Learning a mechanical growth model of flower morphogenesis

Argyris Zardilis, Alexandra Budnikova, Henrik Jönsson

Tools & Resources

CellFateExplorer: An integrated platform for exploring cell fate

Zhaoyang Huang, Haonan Ma, Yuchuan Peng, Chenguang Zhao, Liang Yu

Deep learning predicts tissue outcomes in retinal organoids

Cassian Afting, Norin Bhatti, Christina Schlagheck, Encarnación Sánchez Salvador, Laura Herrera-Astorga, Rashi Agarwal, Risa Suzuki, Nicolaj Hackert, Hanns-Martin Lorenz, Lucie Zilova, Joachim Wittbrodt, Tarik Exner

Inducible, virus-free direct lineage reprogramming enhances scalable generation of human inner ear hair cell-like cells

Robert N. Rainey, Sam D. Houman, Louise Menendez, Ryan Chang, Litao Tao, Helena Bugacov, Andrew P. McMahon, Radha Kalluri, John S. Oghalai, Andrew K. Groves, Neil Segil

pholidosis: an R package to compare biological surface patterns

Isaac W Krone

Temperature-dependence of Early Development of Zebrafish and the Consequences for Laboratory Use and Animal Welfare

Angelina Miller, Katja Lisa Schröder, Karsten Eike Braun, Caitlin Steindorf, Richard Ottermanns, Martina Roß-Nickoll, Henner Hollert, Thomas Backhaus

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