In the second episode of the Human Developmental Biology Initiative’s new podcast, Made the Same Way, science historian Nick Hopwood meets with artist Princess Ari (aka B!TEZ) to discuss how we studied human development in the past and how this field of science is different today.

Throughout the episode, the pair will write and record an original piece of music inspired by their meeting, exploring science in a brand new way.

“Human embryology tells us all where we come from.”

– Professor Nick Hopwood

About the participants

Nick Hopwood is Professor of History of Science and Medicine in the Department of History and Philosophy of Science, University of Cambridge, and a deputy chair of Cambridge Reproduction. He is, most recently, the author of Haeckel’s Embryos: Images, Evolution, and Fraud (Chicago, 2015), which won the Levinson Prize of the History of Science Society, and co-editor of Reproduction: Antiquity to the Present Day (Cambridge, 2018), which is available as a highly illustrated paperback. He has finished a history of human embryos and holds a Leverhulme Major Research Fellowship to write The Many Births of the Test-Tube Baby, a history of claims to IVF. He is a keen walker, runner and gardener.

Princess Arinola Adegbite, professionally known as B!TEZ is a trip-hop singer and rapper from Manchester. The songstress fuses rap, Alternative pop, soulful vocals, and witty spoken word into her Afro-futuristic tracks. She draws inspiration from Nina Simone, FKA Twigs, No Name, Bjork, and Mazzy Star.

B!TEZ is also a multi-award-winning poet, filmmaker, and BBC Words First artist. In 2022 Marco Sebastiano Alessi praised her as an “inventive polymath”. She was awarded Manchester Young Creative of The Year by the Culture Awards for her artistic contributions to the city. She has been commissioned by Selfridges, BBC, British Triathalon, and the University of Cambridge amongst others. She has performed music at Sounds from the Other City, Band on The Wall, Soup Manchester, and the Blues Kitchen. B!TEZ is an MIF Sounds and Youth Music Next Generation Artist. Her debut single ‘Be Like You’ explores the internet’s influence on our identities and self-esteem. The single is from her EP Vintage Destiny and uses organic and electronic sounds to explore the relationship between nature and technology, out on 26/05/2023. 

You can see more of her work here:

• BBC Words First video
• Oral to A4 University of Cambridge
• Our Shakespeare was Tupac Shakur

Please subscribe and listen on Apple podcasts, Spotify, or wherever you get your podcasts. If you enjoy the podcast, please rate and review us on Apple podcasts to help others find us!

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Welcome to #devbiolstories, which I hope will grow into a wholly random collection of short pieces on stuff I want to write about. I also hope you’ll enjoy it.

Today, it’s #devbiolstories Assistant Professor Edition, in which I’ll highlight the work of some of the great new labs in #devbiol. Today, we’ll highlight Erica Hutchins, whose fledgling lab studies chick embryos (get it!) at UCSF.  She’s keen to understand neural crest development and how it might go awry in human disease.

I really enjoyed reading Erica’s awesome preprint with Mike Piacentino and Marianne Bronner about P-bodies and RNA processing in EMT of the neural crest, because I’ve been curious lately about the weird myriad of RNA-based punctae/foci/dots in cells.  Erica’s preprint speaks to the awesome power of modern chick embryology.  So, today’s story is about chickens and the role they played at what we might call the very dawn of mechanistic developmental biology.  It opens, surprisingly enough, with the death of Guy Fawkes.

On January 31^st, 1606, Guy Fawkes famously broke his neck and so avoided being hung, drawn, and quartered, the brutal sentence handed down for his part in the failed “gunpowder plot” to overthrow the British government.  Just a day before, however, his young co-conspirator Everard Digby was not so lucky.  Only twenty-eight years old, Digby’s gruesome death left a wife and two young sons traumatized and destitute.  For the older son, Kenelm, it was only the first episode in a lifetime of extreme drama.

As the Mayflower was sailing to America in 1620, Kenelm was being expelled from Oxford.  He would become a renowned fencer in Italy, personally raid the ships of England’s enemies from Gibraltar to Turkey, and galivant through Paris with René Descartes.  He fled Paris to escape the affections of the Queen of France (or so he claimed, escaping retribution for killing a French nobleman in a duel must also have been on his mind).  It all caught up to him, though, and he spent two years in an English prison.  He was also a developmental biologist.

In prison, Digby worked up a sweeping theory of the natural world, which he published in his 1644 Two Treatises.  Influenced by the rational, mechanical thinking of his friend Descartes, the book’s three chapters on embryology make for astonishing reading.

In the previous story, we learned that chickens have driven #devbiol for millennia, but it was Digby who was the first to use artificial incubation to study them.  Everyone since Aristotle had incubated their chicks under hens.  Aided by Sir John Heydon (“that generous and knowing Gentleman”), Digby built a chick incubator with which “you may lay several eggs to hatch; and by breaking them out at several ages, you may distinctly observe every hourly mutation in them, if you please.”  We do please, Kenelm!

More important by far, however, is that Digby’s studies of the chick led him not only to describe development as others had done before him, but to explain it.  As such, the Two Treatises provide one of the very first attempts at what we might call a “mechanistic” explanation of development.  Clearly, he was gunning for a top journal.

Digby arrived at his novel idea about development (which was at the time called “generation”) by cleverly “considering how a living creature is nourished.”  He wonders:

“Why should not the parts be made in generation of a matter like to that which maketh them in nutrition? If they be augmented by one kind of juice that after several changes, turneth at the length into flesh and bone… why should not the same juice, with the same progress… be converted at the first into flesh and bone though none be there formerly?”

By considering the embryo as a physical entity, fundamentally linked to the very same matter present in our food, Digby gave developmental biology a material basis it previously lacked.  Indeed, most scholars at the time still sought explanations in Aristotle’s two-thousand-year-old framework of ineffable ‘causes’ and ‘humors.’ 

Digby’s work also spurred another scholar, his rather more staid colleague Nathaniel Highmore, to his own studies.  Highmore’s cleverly titled 1651 History of Generation – Examining several opinions of divers authors, especially that of Sir Kenelm Digby… should be more well known, as it was very first to report observations of an embryo using a microscope.  They were chicken embryos, of course.

Highmore extended Digby’s ideas on nutrition, going on to discuss “small indivisible… Atomes” and how they “fall to their proper places, and make up a Chick…” Now, these are not the atoms we know today, but rather an earlier conception whose history we needn’t delve into here.  And of course Highmore and Digby weren’t the only ones studying embryos at the time. William Harvey is by far the most well-known embryologist of the day, but we can talk about him another day.

Suffice to say, Digby and Highmore’s chick studies were important, so let’s put them into context:  To do so, cast your mind back to high school chemistry and Boyle’s Law.  That Law was just one of Robert Boyle’s accomplishments, for he was a pillar of the Scientific Revolution. In fact, his book The Sceptical Chymist is generally considered to mark the dawn of modern chemistry, the science of how things are constituted.  A friend to both Highmore and Digby, Boyle had read their work, and when his own magnum opus was published some ten years after theirs, Boyle noted a key implication of his new chemistry: to “teach us how a Chick is formed in the Egge.”

So, right there, at the very dawn of modern science, at the very moment we began to build a new conception of matter, the humble chicken was already helping to build a new conception of the embryo. 

Digby and Highmore thus tied a crucial knot in the thread that connects Erica Hutchins’ work with chick embryos to Aristotle’s. Two hundred years after Digby and Highmore, Karl Ernst von Baer’s studies of chick embryos would mark the birth modern embryology in the 19th Century.  A few decades after that, in the hands of Wilhelm His, the chick would give up the very first secrets of what we now call the neural crest.  And of course, in the 20^th Century, Nicole Le Dourain and Marianne Bronner, among others, would build the chick neural crest into a massively powerful paradigm for interrogating the mechanisms of embryonic development. 

So, I told this story because I read Erica’s paper and she’s starting a lab with chick embryos, and I wanted to write about how the chicken basically did everything cool in #devbiol for like 3000 years.  But I want to stress here that Erica’s not alone.  I might just as easily have built this story around other new PIs using the chick for cutting-edge #devbiol.  Amy Shyer’s physical/mechanical approach might remind Digby of his friend Descartes; Mike Piacentino’s work on lipid metabolism might get us closer to Digby’s nutritious “juice.”

So let’s be clear, the longest thread in the huge tapestry of #devbiol is still being spun from chick embryos.  And, as Digby wrote, “by drawing the thread carefully along through your fingers, and staying at every knot to examine how it is tied; you see that this difficult progress of the generation of living creatures, is obvious enough to be comprehended.”

Further Reading

This essay, like so many of my obscure obsessions grew from reading A History of Embryology by Joseph Needham.

Digby’s Two Treatises can be found here, and a text searchable version is available from U. Michigan’s Early English Books Online project. Highmore’s History of Generation… is also available as text from EEBO.

Boyle’s The Sceptical Chymist can be read at Project Gutenberg.

For a more thorough accounting of Highmore and Digby’s embryology (and their relation to Harvey), see this piece by Karin Ekholm.

Highmore’s first-ever report of embryos seen through a microscope is discussed here by Bavid Bardell.

And a biography of the fascinating Kenelm Digby is here.

Finally, if you’re keen to really see how developmental biology exploded in the 17th Century, I highly recommend Matthew Cobb’s excellent book, Generation.

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(3 votes)

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In the research paper by Nayelli Marsch-Martínez, Irepan Reyes-Olalde, Antonio Chalfun-Junior and colleagues, we report on the finding of a gene that appears to have been generated de novo, in a specific branch of the plant kingdom (Fig. 1). Some years ago, the idea of genes arising from non-genic sequences was thought to be highly unlikely, since genes were thought to arise from previously existing genes. This gene exquisitely modifies plant growth when overexpressed, causing twisted growth in many organs (Fig 1 or 2). Interestingly, even though this is a recent gene, its loss of function in the model plant Arabidopsis thaliana leads to developmental defects. There are very rare examples of new genes that influence development in such a clear way.

iScience: Twisting development, the birth of a potential new gene

How did you get started on this research?

This research started very long ago. It lasted almost 20 years, with pauses. Nayelli had moved from Mexico to The Netherlands to build an activation tagging population, as part of her Ph.D. (Marsch-Martinez et al., 2002). Many beautiful and interesting mutants were obtained, and other groups came to look for cool phenotypes. The twisted (twt) mutant was discovered by Jurriaan Mes when he came to screen the population and found a plant with siliques growing as helices. Since then, many people have worked on the mutant, first trying to identify the gene that was causing such a curious phenotype. When Nayelli, together with Stefan de Folter, moved to Mexico to work at CINVESTAV-IPN, the mutant came along, and the quest continued there.

What was already known about the twisted gene?

Actually, there was nothing known. We started by isolating the flanking region of the activation tagging element that was causing the phenotype. At that moment, the TWISTED gene was not even annotated. This caused a lot of trouble, because at the beginning, we tried to recapitulate the phenotype by overexpressing other genes, but never got the phenotype. Many constructs and transformants went by and we did not have the gene that was causing the twisted phenotype.

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

Yes, we were happy with the results of the recapitulation experiments, and it was very cool to finally see the recapitulation of the phenotype with the small gene. Also during this period we found that when a silencing construct was introduced into the activation tagging mutant, its phenotype was suppressed, which was exciting.

Another interesting moment was when we finally realized and accepted that this gene was not a common gene, and that probably was present only in a group of plants. This was hard to believe some years ago. A third moment was when the Cas9-edited plants showed phenotypes. We were not expecting that the loss of function of a taxonomically restricted gene would affect development like that. We thought it would maybe be more involved in coping with environmental conditions rather than development itself.

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

The first recapitulation experiments that Antonio (who did the initial experiments) tried, did not produce the phenotype, and this was very disappointing. He did a lot of work overexpressing different genes, analyzing their expression with marker lines and so on, but all the genes he worked on were not responsible for the phenotype. Another difficult moment was when we did the first BLAST searches and did not find any homologous sequences. At that time, these searches would produce zero hits. When Irepan, who also worked on the identification and characterization of the gene, presented the lack of hits in his master seminar, half of his classmates in the auditorium would tell him he was wrong. They could not believe that there was a gene that would not have any homologous sequences in the database. In recent years, we found hits to sequences only from species that are very close to Arabidopsis, but there was nothing at the time when we had just identified the gene.

It was also difficult to obtain a loss-of-function mutant. We ordered T-DNA insertional lines, but they did not cause knock-outs. One, where the T-DNA insertion was located in the UTR, even slightly increased the expression of the gene. Moreover, the phenotypes of silencing lines were not conclusive. It wasn’t until the CRISPR-Cas9 technology was available that we could have a real knock-out.

Where will this story take the lab?

For the moment, the different labs that participated in this study are working on other genes and subjects. We are also focusing on other genes, but we are still working on a side project in collaboration with Luis Delaye, one of our coauthors, to study the evolution of the gene in a more detailed manner. Nevertheless, it would be great to use this gene later in the future to modify fruit shape!

What next for you/your lab after this paper?

We continue to study fruit development and organ development in general, trying to discover new genes that participate in these processes.

Reference:

Marsch-Martinez, N., Greco, R., van Arkel, G., Herrera-Estrella, L., Pereira, A., (2002), Activation Tagging using the En-I maize transposon system in Arabidopsis, Plant Physiology, 129:1544-1556. https://doi.org/10.1104/pp.003327

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We recently announced that we will be working with three newly appointed the Node correspondents, who will be helping us to develop and write content for the Node in 2023. We caught up with each of them to chat about their research backgrounds and the topics that they’re excited to write about over the course of the coming year.

The final member of the correspondents team (which also includes Brent Foster and Alexandra Bisia) is Dina Mikimoto. Dina works as a Postdoctoral Researcher at the University of Tokyo in Japan. She has moved from the field of analytical chemistry into the field of tissue engineering which also involved her moving from Moscow to Tokyo. We discuss the challenges and opportunities that arose from this transition. Also, we talk about the importance of explaining her own work (and work within the wider tissue engineering field) in a clear and concise way – whether to friends or colleagues – and how joining the correspondents team can help her to achieve this goal.

Congratulations on being selected as one of our new the Node correspondents. How did you find out about the role, and why did you decide to apply for it?

I found out about this opportunity while browsing the Node website. During the last year, I’ve been doing quite some thinking about the things I like most about research. I concluded that it is writing papers, drawing schemes for these papers, and then trying to explain the findings in these papers in very simple terms. Actually, I find that many people – whether friends or colleagues – misunderstand what I’m working on which makes explaining my work in a clear and concise way even more important to me.

I was thus looking for ways to communicate my research in a more systematic way. So when I saw this opportunity on the Node, I thought it was a perfect fit. Many of the things that appear on the Node are very close to my heart (and research field!). In my role as the Node correspondent, I hope to surround myself with people who can help me further develop my communication style and help me express myself and my ideas clearly.

Have you done any science writing before, or will this be a new experience for you?

When I was a student in Moscow, I joined a science communication journal for which I wrote a few articles. I couldn’t really choose what to write about though – like one time I was asked to write about sustainable education, and I wasn’t even sure where to start. Of course, it was a really interesting and important topic, but I didn’t feel like I would be the right person to cover it. Instead, I’d rather write about something in which I’ve acquired some expertise and is closer to what I work on.

What is your current research focus? And how did you get into your current position?

I’m originally from Russia where the education system is geared towards mathematics and physics. Biology and chemistry receive less attention, though I was more attracted to these subjects straight away. Initially more to chemistry than biology as I really enjoyed the logical, systematic approach of it. But I was always torn between the two, explaining how I ended up in a PhD in biochemistry in which I studied enzymatic reactions that could be used to help diagnose certain neurodegenerative diseases.

While I was doing my PhD at the Moscow State University, I read a lot of literature about the diseases I was trying to detect with the enzyme-based biosensor I was working on. Rather than just the detection of diseases, I became more interested in work focused on preventing disease. I realised that biochemistry would not be ideally suited for me and I looked for more interdisciplinary fields. It’s how my interest shifted toward the tissue engineering field. Japan is at the forefront of tissue engineering and so I realised this might be the right place for me to go – I wanted to be at the centre of things.  

So I did indeed go to Japan where my supervisor advised me to start another PhD, this time in tissue engineering. Since I finished my first PhD in Russia at the age of 25 – the time when most people in Japan start their PhD studies – I thought why not and decided to go for it. Since then, I have received my 2^nd PhD and now I am trying to build a bridge between my two works.

So you ended up moving from Moscow to Tokyo – what was that like?

I had made some friends in Japan already, including my current husband. When I was doing my PhD in Moscow, a devastating earthquake hit Japan (in 2011). Japanese students at the Moscow State University organised many events to raise awareness of this disaster and I wanted to help in any way I could. I ended up befriending these students (who also studied Russian) and had already visited them a few times before my official move to Japan. It meant that when I moved, I didn’t feel alone at all. Still, it’s very difficult for foreigners to settle down in Japan. They’re very friendly, but there is a lot of difficult paperwork to complete (all in Japanese!).

I was lucky to have my friend, now husband, help me out with the paperwork. Not only this, but there are actually a lot of elderly people who actively help foreigners to settle in. When people retire in Japan, they look for a hobby: for some, this is to help foreigners. So these people know a lot about Japanese society, know nice places to visit (better even than most young people) and speak English really well. In short, they are a treasure of information and made me feel very welcome indeed. The academic atmosphere in Tokyo is also very welcoming and so I was well set up in Tokyo at arguably the epicentre of tissue engineering research.  

Are you planning to write about tissue engineering for the Node? Or are you looking to branch out into other areas?

I would definitely like to write about tissue engineering first. It’s a very fluid research area with influences from many different fields of research. Just in my own lab alone, we have engineers, chemists, programmers, and biologists all working together. I think this mixture of expertise is one of the most exciting aspects of tissue engineering and I’d like to write about the origin of different ideas within this field.

I sometimes feel that tissue engineering is a bit like what the field of “alchemy” used to be: the field that wanted to turn metal into gold. Its goals are perhaps a bit too ambitious at times, but in pursuing ambitious goals many interesting and important observations are being made. Doubtless, the field of tissue engineering will evolve but in which direction is still unclear – which in itself is fascinating.

There are quite a lot of people who have strong feelings about tissue engineering and I’d definitely like to touch on some of the ethical considerations and questions within and surrounding the field. What could be interesting is to compare the regulations across different countries, as I know there is already quite a big difference between Japan and most European countries in terms of regulations.

What are you hoping to gain from the experience of being a the Node correspondent?

One of the things I’d really like to experience is what it is like to be a science writer. In the back of my mind, there is always this voice saying: “you really like to write, so maybe you should write more than you currently do. Maybe you should consider it as a possible career option.” Given my broad background, I do think this could indeed be a good way forward. Last year, when I had a bit more time on my hands, I started Tweeting for my lab, trying to explain the work we’re doing, posting funny videos about fibroblasts etc. I really loved it and look forward to doing more of this kind of work!

Finally, could you perhaps tell us something that people may not know about you? For example, what do you enjoy doing in your spare time?

I love knitting!

Here in Japan, only grannies are supposed to like knitting. But so do I, I guess. Nothing too complicated though, it needs to be relaxing. I mostly make scarfs which I have now given away to many friends and colleagues. They seem to really like them which makes me happy!

Note: You can find all the posts from the Node correspondents here: https://thenode.biologists.com/the-node-correspondents/

(3 votes)

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“It’s like growing a clone of yourself out of your arm,” Bailey Steinworth said, gesturing to her own arm to illustrate one of the ways Cassiopea xamachana — the upside-down jellyfish — reproduces. It’s a sunny day, and we’re sitting at picnic tables outside the University of Florida’s Whitney Laboratory for Marine Bioscience. Steinworth, a graduate student at the Whitney Lab, studies the upside-down jellyfish to understand genes involved in body patterning.

“Actually, you probably wouldn’t want a full clone of yourself,” she amended, “but you might want to grow something else, like a kidney.” Of course, our ability to grow kidneys out of our arms is — pardon the pun — currently beyond our reach.

Steinworth’s example touts the need for a more biologically diverse pool of research organisms to learn about nature’s ingenuity. As “complex” as human beings and other vertebrates are, they don’t always have the biological capabilities of more “primitive” species, such as Cassiopea. On a simpler scale, the upside-down jellyfish lives up to its name with its unique and quirky attributes that makes it, well, so cool.

Cassiopea is a scyphozoan, or “true” jellyfish, that is capable of both sexual and asexual reproduction. As humans, we’re more familiar with sexual reproduction — some of you parents will remember having the talk about the birds and the bees, with its confusing and crisscrossed metaphors making you and your children’s faces turn red.

A fertilized Cassiopea egg produces an embryo that develops into a swimming dot roughly the size of the period at the end of this sentence. This swimming dot, called a “planula,” then settles on the ocean floor as a stationary polyp with tentacles to capture swimming prey. Eventually the polyp will undergo metamorphosis and become a mature adult Cassiopea, or “medusa,” after which the cycle begins anew.

But here’s where things get interesting. At the polyp stage, Cassiopea can undergo asexual budding. These buds are kind of cute, “like tiny little sausage-links on a string,” according to Steinworth. And if you look at these little buds under a microscope, you might notice they look similar to the swimming dot-of-a-planula. And just like the planula, this swimming bud will eventually settle and develop into another polyp.

“When you see a polyp, you can’t tell if it came from a planula or a bud,” Steinworth explained. This observation led her to ask the “big” question that became her PhD dissertation topic: Do asexual buds use the same genes as developing embryos? This question addresses a fundamental gap in the field of developmental biology, and answering it would show one way developmental genes may be used for more than one main purpose during a complicated lifecycle, a possibility that could translate to gene therapies and regeneration research.

But it’s too large and difficult to answer with a single set of experiments. Rather than taking the question as a whole, Steinworth is focusing on a subset of genes thought to be important for body patterning.

As organisms develop, their bodies become regionalized — a fact we may take for granted but which immediately becomes evident when we consider that feet don’t usually grow out of our noses. Over the past century, scientists have identified groups of genes that are necessary for establishing body regions during development. One of these subsets of genes, called Hox genes, is believed to be responsible for establishing what scientists call the “primary axis” (think head to tail).

Steinworth is using this underlying knowledge as a steppingstone to determine whether Hox genes expressed during asexual budding in Cassiopea have the same function as those expressed in a swimming planula. Her first step was to see if the upside-down jellyfish even has Hox genes.

“Hox genes seem to be fairly consistent in most ‘model’ organisms,” Steinworth explained. But it’s less certain what Hox genes might be doing in other organisms like jellyfish that have no clear front and end. Believe it or not, the scientific community still has arguments over questions like “Is the mouth of a jellyfish its anterior or posterior end?” or “How does a jellyfish’s body plan compare to other animals?”

In a recent paper published in Genome Biology and Evolution, Steinworth maps the relation of Hox genes in the upside-down jellyfish to other animals. She hoped that by comparing enough species she could clarify the evolutionary history of Hox genes and get some clear answers about their role in patterning a body plan. Unfortunately, that’s not what happened.

It’s unclear exactly how Hox genes in jellyfish relate to Hox genes in other animals. It’s as though some of these genes have been lost over time, though it’s possible that they just diverged — science-speak for mutating in such a way that they have developed a new function. The true evolutionary scenario, Steinworth notes in her paper, is likely some combination of the two possibilities. There’s just no way to know for sure.

“If I think about it too long, I get lost in the fundamental unknowability of the universe,” Steinworth said with a laugh.

But there are other ways to address Steinworth’s research question. Recently, she’s been conducting a bit of molecular detective work to tease out how Hox genes are expressed in the upside-down jellyfish. Her figures show Cassiopea in various developmental stages with differing patterns of gene expression — a regular “who-dunnit” line-up of every possible Hox gene suspect.

“These expression patterns tell us where and when these genes are expressed,” Steinworth said, “but they don’t necessarily tell us about their function.” That question is Steinworth’s next step in her PhD project, but answering it is not without its own challenges. Because Cassiopea is not an established model organism, most molecular techniques have to be extensively tested and validated before Steinworth can draw any conclusions.

Steinworth’s pursuit illustrates how conducting basic science research can sometimes be a tedious experience, filled with lows and highs of overcoming challenges and discovering the key principles necessary before we can try translating research into something “useful.” At its core, research like this highlights the power of leveraging biodiversity to see what nature is capable of achieving. Progress can be slow when developing tools in new organisms, but patience and perseverance can open doors in ways we can’t predict right away. While humans can’t grow kidneys from their arms (yet), Steinworth’s work will show how developmental genes have evolved and might be repurposed.

“It gives us insight into really early animal evolution,” Steinworth said as our picnic-table conversation draws to a close. “I think that speaks to a fundamental human curiosity to understand what life used to look like.”

(2 votes)

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Dr. Heya Zhao and Dr. Alexey Veraksa at the University of Massachusetts Boston and Dr. Kenneth Moberg at Emory University School of Medicine recently published an article in Developmental Cell where they reveal the non-canonical functions of the Hippo pathway in developmental cell fate decisions in the Drosophila eye. They find that the effect is exerted through the interaction between transcriptional coactivator Yorkie (Yki) and transcriptional intermediary factor 1/tripartite motif (TIF1/TRIM) family protein Bonus (Bon), as well as their regulation of a non-canonical transcriptional program.

1. How did you get started on this project?

When I started as a Ph.D. student in the Veraksa Lab, Alexey and Ken got a new grant on characterizing novel members of the Hippo pathway. We thought that identifying new components of the pathway could expand our understanding of the canonical function of the Hippo pathway in growth regulation and reveal the underlying molecular mechanisms. Given that the transcriptional activity is the ultimate output of the pathway, but the transcriptional machinery was not well understood at the time, we set out to identify binding partners of the transcriptional coactivator Yki through affinity purification-mass spectrometry. In the Yki protein interactome, we identified Bon as a novel interactor, which led us to the identification of completely different functions and mechanisms from what we set out to pursue.

2. Can you summarize your findings?

After identifying Bon in the Yki interactome, we found that Bon interacts with Yki through PPxY motifs in Bon and WW domains in Yki. Instead of regulating tissue growth and embryonic peripheral neuron specification, which represent the independent functions of Yki and Bon, the Yki-Bon complex promotes epidermal fate and antennal fate and suppresses the eye fate. We also studied the Bon interactome and found that the Yki-Bon complex regulates these cell fate decisions by recruiting multiple transcriptional and post-transcriptional regulators, including Sd, HDAC1, Su(var)2-10, Hrb27C, and Svb/Ovo. We then identified genes jointly regulated by Bon and Yki by doing transcriptome analysis, which revealed their repression of Notch targets (e.g. E(spl)-C) and activation of epidermal differentiation genes (e.g. sha, f). We further validated the unexpected repression of E(spl)-C in eye development using transcriptional reporters. This is the first evidence that Yki can function in transcriptional repression in a non-mammalian system. We then showed by genetic analysis that the Yki-Bon complex functions in eye-antenna-epidermis fate determination through their repression of E(spl)-C and activation of sha and f. Altogether, our work revealed a previously unappreciated function of the Hippo pathway in eye-antenna-epidermis fate determination. This function is exerted through the interaction between Yki and Bon, their recruitment of co-regulators, and the transcription of a unique set of target genes (Figure 1).

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

The first result that started to shape the paper was the rescue of Bon-induced epidermal hairs (trichomes) in the eye by knockdown of yki. We spent a long time trying to find a genetic interaction between Bon and Yki by studying their known phenotypes in tissue growth and embryonic peripheral neuron development, but this was unsuccessful. Then, while examining the growth phenotype in adult eyes, I noticed that the eyes look “hairy” under the dissecting microscope when Bon and Yki were overexpressed simultaneously. Upon closer examination with the scanning electron microscope, we identified those “hairs” as trichomes which normally grow on the epidermis but not in the eye. Bon overexpression alone can induce trichome formation in the eye which is enhanced by simultaneous Yki overexpression, but we were not sure if this enhancement was due to the overproliferation caused by Yki. So, it was important to determine whether yki loss of function could rescue the trichome phenotype. When I saw that knockdown of yki or sd almost completely wiped out the trichomes, I was so excited and couldn’t wait to email Alexey the images. Alexey replied: “I think we are onto something with the trichomes.” Turned out that he was right, the trichomes ultimately helped us figure out the deeper mechanisms of cell fate determination in the eye.

Another exciting time was when I completed the RNA-seq data analysis and found the downregulation of Notch targets and upregulation of epidermal genes by Bon and Yki. I was very excited as the gene expression is consistent with the biological phenotypes, and these genes could be the target genes we’ve been searching for. Then, when I saw the beautiful eye-to-antenna transformation resulting from overexpression of dominant-negative Notch in the paper [2] that resembled our double antennae phenotype with Yki overexpression or wts knockdown, I thought this is it! And further genetic tests indeed showed that the functions of the Yki-Bon complex are mediated by these targets.

There are also other exciting moments with experiments, such as seeing the epidermal markers and trichomes in wts mutant clone, the gain of eye fate in bon mutant clones, etc. Sometimes the eureka moments came when having discussions with Alexey and Ken, and we suddenly thought of a perfect experiment that could answer the question or solve the problem. And of course, conversations with other people at conferences always brought great inspirations.

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

The first couple of years were frustrating. We were trying to find a connection between Bon and the Hippo pathway in the known functions and although we knew Bon and Yki interact, we didn’t know the function of the interaction. In the end, we found exciting new functions that they carry out together.  Also, before doing the RNA-seq it was frustrating that we couldn’t identify potential targets from literature reading and data mining. This was resolved after the RNA-seq when we found unexpected non-canonical targets.

5. You used a very broad range of techniques in your paper; did you have any favourites or ones that were more challenging?

I was very lucky to have access to all these resources and have lots of people around me with different expertise who have also been so kind and generous to teach and help me along the way. I love all these approaches, from high-throughput methods and bioinformatics to traditional genetics, as each has its own advantages in answering questions. I found the RNA-seq more challenging at the time since we didn’t have such expertise in our lab before, but it was also an opportunity and I have learned a lot during the process and found myself enjoying deep sequencing data analysis.

6. Where will this story take the lab?

The Veraksa lab is interested in clarifying the exact composition and molecular mechanisms of the multi-protein complexes in which the Yki-Bon module functions. We are also investigating additional functions of the Yki-Bon complex, as well as the functions of Bon and its interactors in various developmental and cellular processes.

7. What is next for you, are you starting a new position?

I have just started my postdoc position with Dr. Oliver Rando at UMass Chan Medical School to study germline and inheritance. I am very excited to explore new areas and expand my skill set.

References:

1. Zhao, H., K.H. Moberg, and A. Veraksa, Hippo pathway and Bonus control developmental cell fate decisions in the Drosophila eye. Dev Cell, 2023. 58(5): p. 416-434 e12.
2. Kumar, J.P. and K. Moses, EGF receptor and Notch signaling act upstream of Eyeless/Pax6 to control eye specification. Cell, 2001. 104(5): p. 687-97.

(1 votes)

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Everyone is different, but we all start as a fertilised egg – we’re made the same way.

Scientists in the Wellcome-funded Human Developmental Biology Initiative are trying to understand more about how the human body is formed from fertilisation to birth. Eventually, this understanding will enable better treatments for many conditions such as heart defects, spina bifida, childhood cancers and infertility. However, human developmental biology is a difficult type of research to talk about – it involves working with human embryos and fetal tissues and the health implications aren’t exactly known yet. 

In our new podcast, ‘Made the Same Way’, young artists collaborate with scientists, embracing challenging conversations about this research. In each episode, an artist creates an original song or poem which echos their feelings and stimulates curiosity about research in human developmental biology. We produced the podcast in collaboration with Reform Radio.

In the first episode, scientist Emma Rawlins meets singer-songwriter Karis Jade to discuss the science of human development. They chat about the basics; what is human developmental biology? Why is it worth studying? And what will it be used for in the future? Throughout the episode, the pair will write and record an original piece of music inspired by their meeting, exploring science in a brand new way.

You can watch a short documentary about the making of the our first episode here.

Please subscribe and listen on Apple podcasts, Spotify, or wherever you get your podcasts. If you enjoy the podcast, please rate and review us on Apple podcasts to help others find us!

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Paris, October 16-19, 2024

The International Conference Centre, Sorbonne Université

This conference is co-organized by the 3 major French organizations in the field: French Society for Cell Biology, French Developmental Biology Society, and Multithematic Institute Cell Biology, Development, Evolution.

It will cover among other the following themes:

• Nuclear architecture, epigenetics, expression genetic

• Cell polarity and embryo axis.

• Cell-Cell interaction, Signaling and patterning

• Cell cycle, growth and Morphogenesis

• Mechanobiology from cell to organs

• Stem cells, adaptation, regeneration, aging

The program will include keynote lectures, invited talks, and many selected talks and posters.

Save the date, information will appear on the websites of the 3 organizers.

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Hello everyone!

I am Joyce Yu, the new Community Manager of the Node. Before joining The Company of Biologists, I was doing science communications at Alzheimer’s Research UK, a charity for dementia research. Prior to that, I did my PhD and a short postdoc in the lab of Jean-Paul Vincent at the Francis Crick Institute, where I studied the role of Wnt signalling in growth and planar cell polarity of fruit flies.

During my PhD, I found the Node to be a useful resource and I enjoyed reading a wide variety of posts on the Node. Fast forward several years, I am now very excited to be joining the Node and contributing to this invaluable community that I once benefited from immensely.

Helen and the previous Community Managers have done an amazing job producing content and engaging with the developmental and stem cell research community. I hope to build on their work and continue working on existing features, while testing out some new ideas and initiatives.

I would like to remind you that once you are registered with the Node, you can immediately start posting on the site. Anyone is welcome to share blog posts, job adverts, and events notice within the community. If you have any ideas or questions about the Node, don’t hesitate to get in touch at thenode@biologists.com or drop me an email.

I look forward to getting to know all of you here at the Node!

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If we’re going to do science communication or science engagement well, we’ve got to do emotions as well as facts. So I think pop culture’s really helpful there.

Dr Jonathan Roberts

In the latest episode of the Genetics Unzipped podcast, we’re taking a leftfield look at public communication of genetics, exploring how the science of DNA turns up in popular culture from comics and music to cakes, with Great British Bake Off winner Syabira Yusoff.

Genetics Unzipped is the podcast from The Genetics Society. Full transcript, links and references available online at GeneticsUnzipped.com.

Subscribe from Apple podcasts, Spotify, or wherever you get your podcasts.

Head over to GeneticsUnzipped.com to catch up on our extensive back catalogue.If you enjoy the show, please do rate and review on Apple podcasts and help to spread the word on social media. And you can always send feedback and suggestions for future episodes and guests to podcast@geneticsunzipped.com Follow us on Twitter – @geneticsunzip

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