A recent paper “Neural crest origin of sympathetic neurons at the dawn of vertebrates” challenges the prevailing dogma that the sympathetic ganglia arose only in jawed vertebrates. Instead, based on the findings in the sea lamprey, the authors suggest a late-developing rudimentary sympathetic nervous system may be present in the earliest jawless vertebrates. First author Brittany Edens and corresponding author Marianne Bronner tell us the story behind the paper.

Wild-caught mature ammocete sourced from the Great Lakes.

How did the project start?

Marianne: Brittany was doing some staining of lamprey larvae with different antibody markers with the goal of defining different types of neurons in the developing enteric nervous system. We got together to look over the data and realized that some of the neuronal staining was not in the gut but dorsal to the gut in a position that was appropriate for the sympathetic nervous system. This was a surprise since lamprey are not supposed to have a sympathetic nervous system. So we started looking for more markers to test this possibility more rigorously.  

Detection of sympathoblasts in late embryonic lamprey: The catecholamine biosynthetic processing enzyme tyrosine hydroxylase (TH) is detected by immunohistochemistry at T27 in (a) transverse sections and (b) lateral whole-mount. TH⁺ sympathoblasts are localized dorsal to the yolk tube and flank the midline in bilateral streams. Scale bars=50mm (a) and 10mm (b).

Why do you think it’s been previously thought that jawless vertebrates lacked the sympathetic nervous system?

Marianne: That’s easy to answer. We think people (including ourselves) were initially looking at the wrong time. In higher vertebrates, the sympathetic nervous system develops rather early in development, initiating when neural crest cells begin to coalesce around the dorsal aorta. We actually looked at comparable stages in lamprey and did not see the markers characteristic of sympathetic neurons co-expressed. However, when we looked at larvae at about 1 month of development, we observed not only sympathetic marker genes but also the transcription factors known to be involved in their specification. Thus, there was a heterochrony in terms of the time of differentiation.

Why did you choose the lamprey to answer your questions? 

Marianne: Lamprey are jawless vertebrates and have an important phylogenetic position at the base of the vertebrate tree of life. Lamprey fossils from the Cambrian period resemble modern lamprey in morphology. While we have no access to a “vertebrate ancestor” and lamprey have continued to evolve, they still are the closest approximation to what we think the ancestor may have looked liked.  

Can you summarise the key findings of the paper in a paragraph?

Marianne: In gnathostomes (jawed vertebrates), the neural crest gives rise to a fate-restricted sympathoadrenal progenitor from which sympathetic neurons of the autonomic nervous system arise. A transcriptional program including Ascl1, Phox2b, and Hand2 specifies neural crest towards sympathoadrenal fates, and also promotes catecholaminergic identity (i.e., expression of tyrosine hydroxylase and dopamine beta-hydroxylase enzymes). Upon maturation, these neural crest-derived sympathetic neurons will express various pan-neuronal genes, as well as genes specific for catecholaminergic function. While the earliest vertebrates, which lacked jaws, were historically believed to lack sympathetic neurons within the trunk, we found evidence of these cells in the jawless vertebrate sea lamprey. We found that the same core transcription factors involved in sympathoadrenal specification were co-expressed in cells throughout the trunk in lamprey, as were the catecholamine pathway enzymes. Later in larval stages, these cells upregulated expression of pan-neuronal markers. Lineage tracing indicated a conserved origin in the trunk neural crest and finally, RNA-sequencing analysis suggested a transcriptional profile that was consistent with sympathetic neuron identity. Altogether our findings challenge the prevailing dogma that the sympathetic ganglia are a gnathostome innovation. 

Were you surprised to find a rudimentary sympathetic nervous system in the lamprey?

Marianne: Yes indeed. We expected to see no sympathetic nervous system since that is what the literature says. It was a real surprise to see neurons in the right place with characteristics of sympathetic neurons.

How does the lamprey’s sympathetic nervous system differ from that in jawed vertebrates?

Marianne: There are many fewer neurons than seen in amniote embryos and no distinct ganglia. Just a few scattered cells all along the trunk region.

Ongoing proliferation of sympathoblasts in lamprey ammocetes: (a-c) HCR detection of Th (teal) and EdU staining (red) in ammocetes following an 8 hour EdU incubation. EdU detection in Th-expressing cells (indicated by arrowhead) reveals active division of sympathetic progenitors/neurons in lamprey trunk into ammocete stages. (d-g) Immunohistochemical detection of TH (teal) and EdU (red) co-expression in transverse sections of ammocetes following an 8 hour EdU incubation. Co-expression is denoted by arrowheads (n-p). DAPI is shown in white. Scale bars=50mm.

Brittany, were there any particular result or eureka moment that has stuck with you?

Brittany: Most of the experiments were performed on late-stage embryos and ammocetes that weren’t much larger, and as a result, a lot of our analyses documented sympathetic progenitors and immature neurons. To get a more mature population of sympathetic neurons for the final sequencing experiment, we actually had to source much larger, older ammocetes directly from the Great Lakes off-season. When they arrived at the lab, I was a bit shocked. They were so much larger than anything I was accustomed to working with, and I wasn’t sure if my tools were even appropriate for the dissections. The long and the short of it: the dissections were fine, but more importantly, the sympathetic trunks of these later-staged ammocetes were visibly discernible under the dissecting microscope. Of course we trusted our data from the late-stage embryos and the younger ammocetes, but I think it’s true that seeing is believing. 

And the flipside: any moments of frustration or despair?

Brittany: When it comes to experiments and data, I try to keep a level head and clear perspective. As scientists, we are after the truth, and every clear result (even the ones we didn’t want or expect) gets us closer to the truth. The scientific process really does work, and having trust in that goes a long way on more challenging days. 

What’s next for you, Brittany?

Brittany: Ultimately, I would like to be an independent investigator. I’m drawn to comparative embryology as a means to understand how peripheral sensory and autonomic neural systems first arose in vertebrates, and how genetic and environmental changes have driven diversification and adaptation of these systems over time. That’s a bit longer term, since I’ve just crossed the three-year mark as a postdoc, but in the meantime we have a collaboration with the Cai Lab at Caltech that I’ve been very excited about. We are looking to leverage their spatial barcoding technology, seqFISH, to better understand neuronal heterogeneity within the peripheral nervous system. Another endeavor I would like to mention is the work I’ve been doing with the support of the Caltech CTLO (Center for Teaching, Learning, and Outreach). One of my goals is to make hands-on science education more accessible to younger students, and with support from the CTLO and feedback from our local high school students, I have been developing grade-appropriate protocols and resources to introduce topics in embryology and neurobiology. 

And Marianne, where will this story take the lab?

Marianne: We are continuing to work on many different neural crest derivatives in lamprey and would like to understand whether the gene regulatory circuits resulting in neural crest differentiation into things like peripheral neurons, craniofacial structures, etc. are conserved to the base of vertebrates. Right now, we are particularly interested in the enteric nervous system and how it has become elaborated. 

(3 votes)

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I can’t believe it has been six months since I started this adventure as a group leader at the Center for Developmental Biology. Since then, few (but also lots of) things have happened.

One of the main things I would highlight is that the lab has grown. We are now four members!

• Andrea Theodorou, who studied her BSc and MSc at Newcastle University, focusing on thyroid cancer and 3D in vitro models of Hepatocellular Carcinoma. She joins the lab as a Research Technician and is already immersing herself in Seville’s culture!

• Irene Carrero Castro, who is completing her MSc in Omic Data Analysis and Systems Biology at the University of Seville. Her MSc thesis focuses on single-cell RNA-seq data analysis and she is being co-supervised by Dr. Fernando Casares and me.

• Grace Wang, who is studying Computational and Applied Math, Data Science and Statistics at Rice University. Since 2022, she has been working on computational and mathematical projects together with Prof. Aryeh Warmflash and me, which hopefully we will be able to announce soon!

Last week we had a very special moment, as we took our first lab picture! Although we missed Grace, as she is located at Rice University, it feels great to be able to show the world the great team that is behind the scenes working on exciting projects. I feel very fortunate to work with these hardworking and brilliant scientists and even better people, and I can’t wait to see what we achieve together. If you want more details about our lab, please have a look at our (also recently finalized) website: https://systemsdevbiolab.com/

We also published my postdoc’s main piece of work on how combinatorial interpretation of BMP and Wnt signals controls cell fate decisions in early human development. Rice University wrote a press release with a nice summary of our work, but if you are interested in more details, you can find our publication here.

Apart from that, these months have been incredibly busy, and I have been trying to understand how to balance all the responsibilities as a new PI. I had heard and partially seen before how many hats one must wear as a PI, but I didn’t fully grasp the meaning of it until I started to experience it myself.

One of the hats that I am the most inexperienced with and that I am learning how to wear is the one involving bureaucratic processes. Although I thought I had seen it all after being an immigrant in a few countries, it seems like there are always things to learn :-) Jokes aside, last month, for example, I learned the steps needed for hiring people in the lab and helping them settle when the candidates are not from Spain. Luckily, with the advice of great colleagues, it all went smoothly, and if anyone is interested, I have made a step-by-step protocol for next time, which I am happy to share. The next bureaucratic step is to learn how to import reagents from abroad; wish me luck!

Balancing these bureaucratic tasks with other responsibilities has been a learning curve. To deal with long to-do lists, I am currently reading a very interesting book called Four Thousand Weeks. Unlike other productivity books, it encourages prioritizing tasks and accepting that time is limited, rather than trying to fit an endless to-do list into a finite day. As my to-do list grows exponentially, I am working on reflecting on what each task would entail before saying yes, even if it initially might seem exciting.

Overall, despite the challenges, I am thrilled with the progress and the new connections I am making. I hope to share some exciting experimental results in my next update. Talk to you soon!

(2 votes)

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Where is the lab?

Our lab is in the center of Budapest, based in the Department of Anatomy, Histology and Embryology, Faculty of Medicine, at the Semmelweis University, Budapest, Hungary.

The Nagy Lab website: https://semmelweis.hu/stemcell/en/

Research summary

Our lab’s principal research goals are to understand the development of the enteric nervous system (ENS) and gut-associated lymphoid organogenesis, using the avian embryo as the model system. The avian embryo is a versatile embryologic model that we have leveraged to identify the role of multiple factors on the migration, proliferation, and differentiation of enteric neural crest-derived cells as they colonize the intestine to form the ENS. Abnormalities in this process lead to neurointestinal diseases like Hirschsprung disease, a congenital disorder in which ganglion cells fail to develop in the distal gut, leaving newborns with a bowel obstruction. We perform a variety of avian embryologic methodologies, including chimeras, parabiosis, gene overexpression and gene silencing studies using siRNA-RCAS viruses to examine the role of the extracellular environment in the embryonic gut that regulate the mechanisms of neural crest derived stem cell differentiation during intestinal morphogenesis.

Secondly, our lab focuses on mechanisms that underlie lymphoid organ formation. This work also uses the avian embryo as the model system, and addresses the cellular, molecular, immunological and morphological aspects of the primary and secondary lymphoid organ formation. Our aim is to discover how the avian lymphoid organs are built, and how immunosuppressive diseases affect their organization.

Lab roll call

Nándor Nagy: As the head of the lab, my primary task is to ensure that everyone is enthusiastic about coming to the lab each morning. As a PI, I train the research staff to have the skills to execute research protocols competently. I am also a university professor responsible for leading the developmental biology course and teaching human anatomy classes for medical students.

Katalin Kocsis, associate professor: With decades of experience in teaching anatomy, histology, and embryology, I help students understand the complexity of the developing embryo. I am also providing the administrative background to our Developmental Biology course for medical students in both Hungarian and English programs.

Nóra Fejszák, post-doc: Using the avian embryo as a model system for early hematopoiesis, I investigate yolk sac stem cells in multiple avian species and their differentiation to tissue resident immune cells.

Viktória Halasy, PhD student: Currently I am writing my PhD thesis about the development of the extrinsic innervation of the colorectum.

Ádám Soós, PhD student: My main project is to establish the enteric neurosphere technique in the avian model system. I am responsible for the microscopy facility of our laboratory.

Emőke Szőcs, PhD student: I work towards understanding the inductive capacities of embryonic tissues and cell-cell interactions in forming primary lymphoid organs.

Zsanna Gecse, undergraduate student: As a third-year medical student, my task is to study the complexity of hindgut innervation, currently characterizing a new cell type in the mucosa of the avian hindgut.

Csenge Jurenka, undergraduate student: I joined the lab in the second year of medical school; I am trying to establish a novel Hirschsprung’s disease model to understand enteric neurocristopathies better.

Ábel Farkas, undergraduate student: I am a second-year veterinary medicine student. Since joining the lab, I started characterizing the development of the cloaca-associated lymphoid structure in domesticated birds.

Zsófia Bogya, undergraduate student: My student research project is to study the development of the dendritic cells in chicken primary lymphoid organs.

Réka Borbála Tóth, undergraduate student: I study bioengineering and try to understand the role of extracellular matrix proteins in the migration of enteric neural crest-derived cells.

Noémi Kegyes, lab assistant: I help with all ongoing projects in the lab, making sure everyone can continue their work with a smile on their face.

Favourite technique, and why?

Nándor: My favorite techniques in studying the embryo are microsurgery and imaging. Avian embryos are accessible during all stages of embryogenesis and there is a large repertoire of methodologies, including tissue grafting, retroviral-mediated gene transfer, electroporation, and embryo culture I use to perturb and analyze gene function during development. Microscopy is the best way to show the complexity of the developing tissues and organs. Analysis of both live organ cultures and fixed tissue samples using transgenic lines or multiplex immunofluorescence, complemented by microscopy at different resolutions enables the examination of developing organism across various scales, from intracellular ultrastructures to complex multicellular tissues.

Apart from your own research, what are you most excited about in developmental and stem cell biology?

Nándor: I believe that being a stem cell and developmental biologist at this time is filled with excitement. While there has been significant progress in studying the embryo, the underlying biology and causes of many congenital diseases are still not well comprehended. By combining various techniques and resources, adopting a multidisciplinary approach that includes careful clinical phenotyping, genetics, developmental biology, and regenerative medicine, we have the potential to truly advance our understanding and stem cell treatment of congenital diseases within the next 5-10 years. Our goal is to be at the forefront of this important endeavor.

How do you approach managing your group and all the different tasks required in your job?

Nándor: I am privileged to lead this lab with highly motivated young scientists driven by their unique interests. Balancing between administrative and teaching tasks, I always enjoy working with my PhD and undergraduate students in the lab. Enthusiasm and fun are essential in science, and I believe lab members should be self-motivated, choosing projects that interest them. I dedicate time to help new students to acclimatize to the lab and encouraging them to find a topic to study and develop new ideas over time. Weekly lab meetings, joint lab meetings with other research groups and spontaneous discussions provide a strong foundation for our work and support the collaboration between the lab members. In addition, one-on-one meetings with lab members ensure their individual success, which I highly prioritize.

What is the best thing about where you work?

Nándor: The familiar atmosphere and numerous opportunities for scientific collaboration with other research labs in Hungary and internationally.

Katalin: In this lab one can always get the help and encouragement that is needed to be successful in the academic and educational fields.

Nóra: It is great to encounter the wonders and fragility of life almost every day through chicken embryos enclosed in eggs, and I have the opportunity to share this experience with a cohesive and supportive lab team in which new and exciting ideas are generated continuously.

Viktória: Our lab community exudes enthusiasm, cheerfulness, and unity, resembling a tight-knit group of friends, thanks to exceptional leadership. We prioritize teamwork and the sharing of thrilling new findings.

Ádám: The environment is very cozy, the lab members are really supportive. It’s a bit like a second family.

Emőke: Trying to understand the developing embryo is such an exciting task. We approach this with the most diverse methods, which makes day to day lab work so much fun – all while doing this with a great team.

Csenge: Whenever I am working in the lab, there is always someone to ask for help, get some advice from, or just have a chat with, and this gives me a lot of motivation.

Zsanna: Working in the lab is a fantastic opportunity for me to familiarize myself with laboratory techniques that I would not normally study and to deepen my knowledge in the field of embryology. I also love the fact that whenever I go there, I see the smiley faces of my coworkers who are always there to help me with any difficulty.

What’s there to do outside of the lab?

Nándor: I love the vivid Budapest city and always enjoy its historical and multi-cultural hub character. I grew up in Transylvania (8 hours from Budapest), a historic eastern European region with truly wild mountain region, a land that is still rich in myths and legends. I love to go mountain hiking, visit castles and ruins, discover the various biodiversity, and spend time outdoors with my family. Budapest and Transylvania are the places to be!

Katalin: Living in the suburban part of the city with my family, we enjoy gardening around the house. Visiting the central part of the city is always like an interesting tour. Theatres, museums, the zoo – several exciting places to see frequently – not only in Budapest – but also in other parts of Hungary.

Nóra: Budapest is full of colorful life and offers a wide range of exciting indoor and outdoor activities. On workdays we sometimes go out for a coffee or an ice cream to a nearby park. During weekends I like to explore the hidden natural formations of forests around Budapest with my family. My favourite ones are the forests that belong to the floodplain of the river Danube.

Viktória: Beyond the lab, attending conferences and weekend trips always leads to memorable moments. During weekdays at night, we frequently chill out with activities like indoor rock climbing or ice skating in Városliget, the central park of Budapest.

Ádám: Our lab is close to the city center, making it convenient for us to unwind together outside of work. Whether it’s grabbing a drink at a local spot or engaging in activities like bouldering or hiking, there’s no shortage of options for us to bond and relax together.

Emőke: Budapest is a vibrant place; both city life enthusiasts and outdoorsy people can find activities to their taste. Just take a walk along the Danube in the evening, enjoy concerts, discover art galleries and museums, explore nature in the hills around Budapest, try kayaking on the river and have fun!

Csenge: There are some great bars near the lab, where we can celebrate after a successful conference, but Budapest itself gives great joy with its monumental buildings and wonderful scenery along the Danube.

Zsanna: I find Budapest the perfect place to be a university student, as the city is famous for its nightlife as well as its monumental historical heritage. Whether you are an extrovert who wants to meet friends every weekend at a new pub, or an introvert who wants to get lost in the museums, you will find your place here.

(4 votes)

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In the May Development presents… webinar, we celebrated the winners of Development’s 2023 Outstanding Paper Prize. Catch up on the recordings of the talks from the authors of the two winning papers.

Ling Loh (The George Washington University) &
Joe Hanly (The George Washington University and Duke University)

Megan Michalski (Van Andel Institute)

(2 votes)

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Do you know about Development’s ‘at a glance’ article types? These articles comprise a short text document highlighting the fundamental aspects of a developmental biology topic, which is accompanied by a large poster schematic that illustrates all you need to know ‘at a glance’.

Development has published a number of these articles over the years, ranging on topics from somitogenesis to gibberellin signaling, branching morphogenesis to the peripheral nervous system. To view the full collection, visit this page.

Some of most recent, free-to-read articles are included below; to download the high-resolution image, click on the link in the ‘High-resolution poster’ or ‘Supplementary Information’ section of the online article. If you’d like your own physical copy of a poster to hang in your lab or office, look out for The Company of Biologists’ exhibit at the upcoming Society for Developmental Biology meeting (Atlanta, GA, USA) or the ISSCR annual meeting (Hamburg, Germany).

Insulin signaling in development

Miyuki Suzawa, Michelle L. Bland

 This Development at a glance article summarizes insulin hormone family signaling and highlights the roles of individual hormones in regulating growth, cell proliferation and differentiation.

The peripheral nervous system

Aliia Murtazina, Igor Adameyko

This Development at a Glance article provides up-to-date basic knowledge of the anatomical and functional organization of the peripheral nervous system (PNS), with additional insights into the development and cell-type heterogeneity underlying its different roles.

Notch signaling in development and homeostasis

Oren Gozlan, David Sprinzak

A brief overview of the Notch signaling pathway and its molecular activation mechanism, discussing different examples of Notch-mediated coordination of differentiation between neighboring cells during development and homeostasis.

Hox genes in development and beyond

Katharine A. Hubert, Deneen M. Wellik

This Development at a Glance article provides an overview of the genomic organization, protein structure and regulation of Hox genes and our current understanding of their roles both during and after embryogenesis..

Resolving morphogenesis into quantifiable cell behaviours

Jeremy B. A. Green

This Development at a Glance article describes how a cells’ limited repertoire of behaviours provide the basis for quantifying morphogenetic phenotypes.

Human assembloids

Sabina Kanton, Sergiu P. Paşca

This Development at a Glance article gives an overview of the potential of assembloids – three-dimensional, self-organizing in vitro cell culture systems constructed by integrating organoids or organoids and other cell lineages.

Biology of resident tissue macrophages

Christopher Zhe Wei Lee, Florent Ginhoux

This Development at a Glance article gives an overview of the ontogeny, maintenance and unique tissue adaptions of macrophages, and highlights their role in development, homeostasis and dysfunction.

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In the paper “Distinct stem-like cell populations facilitate functional regeneration of the Cladonema medusa tentacle”, Fujita and colleagues found that the mechanism of tentacle regeneration in jellyfish is more similar to how salamanders regenerate their limbs than how other cnidarians regenerate. First author Sosuke Fujita and corresponding author Yuichiro Nakajima tell us more about the story behind the paper.

How did the project get started?

It has long been known that jellyfish organs like the manubrium and the tentacle can regenerate, but the detailed mechanisms at the cellular and molecular levels remain unclear. Using the hydrozoan jellyfish Cladonema pacificum (Figure 1), we began this study by examining the regenerative potential of each organ and found that tentacles have a high regenerative capacity, functionally regenerating within 2-3 days, which exceeded our expectations. We anticipated that the Cladonema tentacle would be a useful model for studying appendage regeneration and aimed to comprehensively understand its mechanism. To this end, we decided to monitor regeneration processes including wound healing, cell proliferation, stem cell distribution, and the timing of cell differentiation over time. In particular, we found that cell proliferation occurs intensively at the site of injury in the early phase of regeneration after wound healing completes. Based on these observations, we asked the simple question, “How do proliferating cells appear at the site of injury?”

What is known about blastema formation during regeneration before your work?

Blastema is an aggregate of cells that includes undifferentiated cells like stem cells, serving as a cellular source for regeneration. Blastema formation is a critical step for regeneration, occurring in regenerative animals like planarians, salamanders, and cnidarians, which are among the early-branching animals. However, methods of blastema formation, particularly the way of supplying undifferentiated cells, vary among regenerative animals, and the evolutionary aspects of the process remain unknown. While it is ideal to understand the mechanism of blastema formation across diverse animals, our knowledge about it in basal metazoans is mainly limited to a few polyp-type models, such as Hydra and Hydractinia (Bradshaw et al., 2015; Chera et al., 2009). We thus focused our attention on blastema formation during organ/appendage regeneration in jellyfish. Understanding this mechanism in jellyfish allows us to compare it with cnidarian polyps as well as some regenerative bilaterians.

Why did you choose the jellyfish Cladonema pacificum as your research organism?

Cladonema pacificum is a small jellyfish (less than 1 cm in height) widely found along the coast of Japan with a typical hydrozoan life cycle including the polyp and medusa stages (Figure 2). The Cladonema medusa is basically benthic, and all the stages are easily kept in small containers without any special equipment. This organism can be stored at 4°C for years as stolons (structures connecting polyps) as a dormant stage, which can reproduce polyps and medusae once returned to a warm temperature (e.g., 22°C), making maintenance easier. We are able to keep this jellyfish in our laboratory, which is located far from the sea. Importantly, Cladonema has the ability to regenerate organs, especially lost tentacles, in just a few days (Fujita et al., 2019). These factors made Cladonema an ideal model for studying organ regeneration in jellyfish.

Can you summarize the key findings of the paper in one paragraph?

Based on previous studies using polyp models, blastema formation in cnidarians was thought to utilize the recruitment of resident pluripotent/multipotent stem cells. In contrast, we found that repair-specific proliferative cells (RSPCs) with stem cell characteristics appear upon amputation and are mainly involved in blastema formation during tentacle regeneration. Additionally, RSPCs preferentially differentiate into epithelial cells in the newly regenerating tentacle, while resident stem cells supply all the cell types including cnidocytes, promoting functional tentacle regeneration. These results suggest that blastema formation during Cladonema tentacle regeneration is analogous to limb regeneration in newts, rather than cnidarian polyps (Figure 3; Fujita et al., 2023). Our findings imply a common mechanism for supplying repair-specific blastema cells for complex organ regeneration that has independently evolved in each animal phylum.

Were you surprised to find that most blastema cells do not come from resident stem cells but instead from repair-specific proliferative cells (RSPCs)?

Yes, we were surprised. We had initially expected resident stem cells to migrate and form blastema as seen in other cnidarian polyp systems during whole-body regeneration. We were puzzled when the nucleoside chase experiments showed unexpected results. We thus needed additional evidence to clarify this: for example, we found that RSPCs can still appear even after eliminating resident stem cells with X-ray irradiation or drugs. During the revision process of the paper (Fujita et al., 2023), we addressed numerous concerns related to this issue with further experiments, which strengthened our observations.

Can you postulate the cellular origins of the RSPCs?

Yes, we believe there are at least two possibilities: one is the reactivation of quiescent stem cells and the other is dedifferentiation. Similar to satellite cells in vertebrate muscle, damage can reactivate their cell cycle to become RSPCs, giving rise to differentiated cells. Alternatively, upon injury stimulus, differentiated cells can revert to RSPCs with an undifferentiated state via dedifferentiation, becoming able to proliferate. We are trying to figure out which is the case for tentacle regeneration.

Were there any other unexpected results and challenges, especially associated with working with a non-model research organism?

Working with non-model animals presented various challenges. Existing protocols for other models, even cnidarians, often require modification, and establishing experimental methods can be time-consuming (Fujita et al., 2022; Masuda-Ozawa et al., 2022). Additionally, some common knowledge does not apply to specific animals and contexts: for instance, some marker genes are not expressed in expected cell types, and their expression can be heterogeneous among tissues and locations, which initially became an issue. After rounds of investigation and consideration, these unexpected results eventually provide insights into the differences between what we observe and what is already known. Overall, the experience of working with a non-model research organism has been more enjoyable than challenging.

What are the implications of your findings in understanding regeneration in other organisms?

Our findings (Figure 3) imply that blastema can be supplied by repair-specific stem cell populations, similar to those observed in salamander limb regeneration (Sandoval-Guzman et al., 2014), rather than by resident stem cells, which previous cnidarian studies had focused on (Amiel et al., 2019; Bradshaw et al., 2015; Chera et al., 2009). Furthermore, the heterogeneity of stem cells discovered in the context of regeneration might also be identified during development and homeostasis in cnidarians or basal metazoans. Investigating how stem cells contribute to regeneration and how blastema forms during regeneration across different cnidarians will enhance our understanding of the evolutionary trajectory of the blastema formation program.

What’s next for this story and your lab?

We want to understand how the two stem cell populations we identified are regulated differently during regeneration. Our lab is currently identifying the signaling pathways that control cell proliferation and differentiation in each cell population. We also aim to determine how RSPCs emerge, especially their cellular origin. To distinguish different possibilities, we are designing new experiments and developing genetic tools in Cladonema. These approaches will provide a better understanding of regenerative processes at the molecular level and enhance our ability to explore diverse phenomena in jellyfish.

References:

Amiel, A. R., Foucher, K., Ferreira, S. and Röttinger, E. (2019). Synergic coordination of stem cells is required to induce a regenerative response in anthozoan cnidarians. bioRxiv, 2019.2012.2031.891804. 10.1101/2019.12.31.891804

Bradshaw, B., Thompson, K. and Frank, U. (2015). Distinct mechanisms underlie oral vs aboral regeneration in the cnidarian Hydractinia echinata. Elife 4, e05506. 10.7554/eLife.05506

Chera, S., Ghila, L., Dobretz, K., Wenger, Y., Bauer, C., Buzgariu, W., Martinou, J. C. and Galliot, B. (2009). Apoptotic cells provide an unexpected source of Wnt3 signaling to drive hydra head regeneration. Dev Cell 17, 279-289. 10.1016/j.devcel.2009.07.014

Fujita, S., Kuranaga, E., Miura, M. and Nakajima, Y. I. (2022). Fluorescent In Situ Hybridization and 5-Ethynyl-2′-Deoxyuridine Labeling for Stem-like Cells in the Hydrozoan Jellyfish Cladonema pacificum. J Vis Exp. 10.3791/64285

Fujita, S., Kuranaga, E. and Nakajima, Y. I. (2019). Cell proliferation controls body size growth, tentacle morphogenesis, and regeneration in hydrozoan jellyfish Cladonema pacificum. PeerJ 7, e7579. 10.7717/peerj.7579

Fujita, S., Takahashi, M., Kumano, G., Kuranaga, E., Miura, M. and Nakajima, Y. I. (2023). Distinct stem-like cell populations facilitate functional regeneration of the Cladonema medusa tentacle. PLoS Biol 21, e3002435. 10.1371/journal.pbio.3002435

Masuda-Ozawa, T., Fujita, S., Nakamura, R., Watanabe, H., Kuranaga, E. and Nakajima, Y. I. (2022). siRNA-mediated gene knockdown via electroporation in hydrozoan jellyfish embryos. Sci Rep 12, 16049. 10.1038/s41598-022-20476-1

Sandoval-Guzman, T., Wang, H., Khattak, S., Schuez, M., Roensch, K., Nacu, E., Tazaki, A., Joven, A., Tanaka, E. M. and Simon, A. (2014). Fundamental differences in dedifferentiation and stem cell recruitment during skeletal muscle regeneration in two salamander species. Cell Stem Cell 14, 174-187. 10.1016/j.stem.2013.11.007

(2 votes)

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A Press Release from Development

No parent wants to risk their child having a serious infection, least of all while still in the womb, but did you know that the immune response to a viral infection during pregnancy could also affect the development of the unborn offspring? Scientists from Harvard University in Cambridge, USA, have shown that immune reactions in pregnant mice are detected by a specific type of brain cell in the developing embryo and alter how genes are regulated in the brain – a change that persists in juvenile mice. Published today in the journal Development, this study provides new insights into how the maternal immune response might influence brain development in embryos and could help researchers understand the origins of neurodevelopmental disorders such as autism.

Scientists have long suspected that fetal exposure to infectious bugs may increase the risk of developing neurological conditions such as schizophrenia and autism spectrum disorders. There is also evidence that fighting infection while pregnant might affect the growth of offspring in the uterus, even if embryos do not become infected themselves. However, it has been unclear how embryos recognise their parent’s immune response and the exact consequences for their development.

In their latest study, a group at Harvard University led by Professor Paola Arlotta have identified a specific cell type in the mouse embryonic brain that responds to an immune response in the mother. The researchers used a compound that mimics a virus to stimulate an immune response in pregnant mice without causing an actual infection. They then characterised how cells in the embryonic brain respond by assessing which genes were turned on or off. Using this approach, the scientists showed that cells called ‘microglia’ can sense the maternal immune response. “Microglia are the immune cells of the brain. They play a critical role during inflammation and infection and also have fundamental functions in healthy brain development,” explained Arlotta.

Following the mother’s immune response, embryonic microglia change which genes are activated or inactivated, which also occurs in the surrounding brain cells, such as neurons. Interestingly, the change of gene regulation in neighbouring cells depends on microglia being present in the brain; when the researchers repeated the experiments using mice without microglia, the other brain cells did not react to the maternal immune response.

Although most viral infections are often short-lived, the scientists found that the changes that the maternal immune system causes in embryonic brain cells persist well after the immune reaction has subsided. “Based on previous studies demonstrating that microglia exposed to early infections respond differently to stimuli in adulthood, we hypothesized that the maternal immune response could induce changes in microglial gene regulation that persist postnatally” said Dr. Bridget Ostrem, co-author of the study.

This research enhances our understanding of the cellular basis of neurodevelopmental disorders in humans. “Our results suggest a potential role for microglia as therapeutic targets in the setting of maternal infections,” said Ostrem, although there is still more work to be done. Harvard researcher Dr. Nuria Domínguez-Iturza added, “next, it will be crucial to determine the long-term behavioral implications of the changes we observed in this study.”

Ostrem, B. E. L., Domínguez-Iturza, N., Stogsdill, J. A., Faits, T., Kim, K., Levin, J. Z. and Arlotta, P. (2024). Fetal brain response to maternal inflammation requires microglia. Development, 151, dev202252. doi:10.1242/dev. 202252

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Where is the lab?

Daniel Kierzkowski: Our lab is part of the Plant Science Research Institute (fr. Institut de Recherche en Biologie Végétale – IRBV) established through a partnership between the University of Montréal and the City of Montréal. We are located in the beautiful Montréal Botanical Garden.

Institute website: irbv.umontreal.ca/?lang=en

Lab website: kierzkowski-lab.com/

Research summary

Our group studies the fundamental aspects of plant organogenesis. We aim to understand how tiny primordia, composed of groups of undifferentiated cells, give rise to the amazing diversity of organs found in nature. Using model systems such as Arabidopsis and Physcomitrium, we seek to uncover how fundamental processes of cellular growth, patterning, and differentiation are controlled at the molecular, cellular, and tissue levels to produce specific shapes. We hope that our research will provide a foundation for future crop improvement.

Lab role call

Wenye Lin: I am a Ph.D. student in the lab since 2020. The tiny moss Physcomitrium patens is my best friend. I study the evo-devo aspect of organ development with a focus on the role of auxin in regulating moss leaf (phyllid) morphogenesis.

Elvis Branchini: I am interested in plant development, genetic editing, and synthetic biology. My Ph.D. project aims to uncover the growth dynamics and regulation of primordia initiation in Arabidopsis thaliana.

Amelie Bauer: I am a Post Doc investigating the mechanisms behind the initiation of the valve margin structure in Brassicaceae fruits.

Binghan Wang: My Ph.D. project focuses on studying the gynoecium development of Brassicaceae species. Specifically, I investigate the roles of hormones and mechanical forces in fruit shape establishment.

Benjamin Lapointe: I am a Ph.D. student working on the development of the leaf in Arabidopsis thaliana. I use genetics, novel imaging methods, and mathematical analysis to decipher the processes shaping leaf growth and morphology.

Xuan Zhou: I am a visiting PhD student from Xishuangbanna Tropical Botanical Garden, Chinese Academy of Sciences. My project investigates the development of leaf shape during primary and secondary morphogenesis.

Sylvia Silveira: I spent four years as a postdoc in the lab and now transitioned into a research professional. While being involved in other projects from the lab, my focus is on exploring how organs get their 3D shapes using stamen as model system.

Rachelle Fontaine: I am a Master 2 internship student in the lab. I work on understanding shoot apical meristem growth in A. thaliana and how it is related to auxin.

Favourite technique, and why?

Daniel: No doubt: confocal microscopy! Our lab specializes in confocal time-lapse imaging, which allows us to follow organ development at cellular resolution for extended periods (up to two weeks of growth). When combined with image analysis software like MorphoGraphX, we can quantify cellular growth dynamics on the organ surface and, more recently, in 3D. This powerful approach helps us precisely understand how molecular and cellular behaviors translate over time into the final organ shape.

Apart from your own research, what are you most excited about in developmental and stem cell biology?

Daniel: Synthetic biology is fascinating. It’s amazing how animal stem cells can self-organize in vitro to spontaneously form early embryos or simple organs. I am also excited to see new model systems emerging in plants, which will allow us to answer important evolutionary questions in the near future.

How do you approach managing your group and all the different tasks required in your job?

Daniel: As a university professor, my job involves constant multitasking, from teaching undergraduates to managing the lab. I try to focus as much as possible on my research group. I want to be directly involved in all research projects while giving the people working with me enough freedom to pursue their own ideas. I strongly believe in teamwork and aim to create a collaborative environment that stimulates scientific interaction within the lab and with collaborators. Home office is not my thing; I try to be in the lab whenever possible. I am convinced that exciting discoveries can be achieved only when people work together to exchange ideas, troubleshoot problems, and support each other.

What is the best thing about where you work?

Benjamin: The multidisciplinary approach to biology, combining molecular tools, microscopy, and a biophysics perspective. Applying mathematics and modeling to extract new information is very exciting. To be at the edge of what has been done and what can be achieved in science.

Wenye: I love the location of the lab in a botanical garden, in our case, the largest one in north America. I am also spoiled by the amicable atmosphere between colleagues and supervisors.

Elvis: The best thing about where I work is the dynamic lab exchanges that keep us always thinking about the common patterns of development in general, how to make better experiments, and how to present it properly and succinctly. Also, the lab being at the Montreal Botanical Garden is a great perk!

Amelie: I like the effervescence of collaborative and interdisciplinary work that is at the root of our laboratory’s scientific dynamism. Fueled by a positive and friendly atmosphere, we can engage in multiple projects aimed at enhancing our understanding of plant morphogenesis.

Sylvia: I appreciate how collaborative everyone in the group is, and I love the inspiring location of the lab, within the Montreal Botanical Garden.

Rachelle: What is amazing in the lab is the collaborative and interdisciplinary work environment. Everyone is always willing to share their knowledge and help, leading to many exciting discussions and reflections.

Daniel: It is not so much about where but with who I work. I am super lucky to work with amazing people that are passionate about science.

What’s there to do outside of the lab?

Daniel: Montreal is a vibrant and multicultural city where everyone can find something interesting to do. We are privileged to have numerous festivals and cultural activities throughout the year, especially in the summer. The surrounding nature is outstanding. Although Canadian winter can be intense, there are plenty of outdoor and indoor activities to help us get through it.

Amelie: We are located in the Botanical Garden, a unique place where you can admire the diversity of the plant world. With its spectrum of sporting, cultural, and intellectual activities, Montreal reveals itself as a vibrant and surprising city. Close to immense natural parks, its location allows easy access to the great outdoors and an easy escape from the city.

Wenye: Montreal is a green gateway to nature. Besides having the Botanical Garden as our backyard, our lab is also within walking distance of the Olympic Park and the large Maisonneuve Park. The world-famous Niagara Falls and popular whale-watching spots are also nearby. Afraid of the long winter season? You will easily fall in love with the winter sports opportunities Montreal generously offers, such as downhill or cross-country skiing, ice skating, and snowshoeing. Montreal is also rich in cultural events, offering a variety of museums, concerts, and performances.

Binghan: Montreal offers several free public facilities, such as tennis courts in the summer, skating rinks in the winter, and indoor swimming pools available year-round. I appreciate how multicultural this city is, providing a fascinating exploration of diverse histories and food cultures from various nations.

Sylvia: Discover the diverse international culinary scene and local breweries. Go cycling, have picnics in the parks, explore museums, enjoy numerous festivals, hike in nearby national parks, and experience winter sports.

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Development’s Deputy Editor Steve Wilson (UCL) hosts three early-career researchers studying brain development

Wednesday 5 June – 15:00 BST

At the speakers’ discretion, the webinar will be recorded for viewing on demand. To see the other webinars scheduled in our series, and to catch up on previous talks, please visit: thenode.biologists.com/devpres

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Introducing the Node’s new search and filter function.

Just over a year ago, I was applying to become the Node’s Community Manager. One of the pre-interview tasks was to come up with ideas for the Node, so I wanted to look back at what’d been done already. While I enjoyed discovering random posts from the early days of the Node, I quickly realised that the search function was rather limited: I could only filter by date or category, and it wasn’t possible to filter by date and category.  

Now, I’m delighted to introduce our brand new ‘Advanced search’ function, where you can search and filter by category, tag, author and date. Thank you to the team working behind the scenes to push out this new search tool!

As the Node approaches its 15^th anniversary in 2025, we hope this new search function will allow long-time and new readers alike to enjoy all the weird and wonderful posts the Node has put out since 2010.

Have a go and let us know what you think! What else would be useful to you, our dear Node readers, to include in the search functionality?

Do you know

… we have a new Search button:

Click the Search button in the menu bar to go to the ‘Advanced search’ page.

… you can filter by category, tag, author and date:

For example, I wanted to search for ‘behind the paper’ stories that mention Wnt signalling, my favourite signalling pathway. I can type ‘Wnt’ in the search bar and filter in Tags by ‘behind the paper’.

… you can search for all the posts someone has written:

I found out the first ever Community Manager of the Node, Eva Amsen, wrote a total of 141 posts!

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