The animation is a result of collaborative work of scientists from the Novo Nordisk Foundation Center for Stem Cell Biology (DanStem) and visual storytellers from the Animation Workshop (VIA), telling the story of a scientific attempt to learn what happen to the liver when damaged and how this knowledge could be translated in the future and help healing liver diseases and improve patients quality of life.

(2 votes)

Loading...

One night, during the summer of 2012, I found myself sitting in a cottage in Woods Hole, trying to explain to my parents why I’d spent much of my professional life studying the little skate (Figure 1). I was a postdoctoral fellow at Dalhousie University at the time, and working almost exclusively with skate as a model system was hard: I could only access animals while visiting the Marine Biological Laboratory (Figure 2), and while I was fortunate enough to spend my summers in Woods Hole (thanks largely to generous support from the MBL Whitman Center Fellowships programme and the MBL Embryology Course), there were relatively few tools and resources available for the skate at that time, and limited access to animals meant that I was under a great deal of pressure to design, optimise and complete experiments during a relatively short time window each year. Why would anyone do this to themselves?!

Up until that point, I’d worked exclusively on skate embryonic development. I explained to my parents that skates occupied a very important position in vertebrate evolutionary history, and that by studying skate embryos, and comparing our findings with what we know from work in mouse, chick, frog and zebrafish, we are able to make inferences about anatomical features (and developmental mechanisms) that were present in the last common ancestor of jawed vertebrates. That’s a perfectly good and valid reason for studying skate embryos, isn’t it? So why was I getting the “blank look” that many of us scientists know and dread? Could it be that aspiring to infer ancestral developmental mechanisms, while a perfectly good and reasonable academic endeavour, is not necessarily the most compelling reason for studying an obscure marine organism, in the eyes of a non-scientist? Like a stand-up comic squaring off against a heckler, I felt the need to come up with something else – and fast.

Sometimes, such moments of forced introspection push us to recognise things that we’ve long known, but rarely acknowledge. I started to think about how, for as long as I could remember, I’d been drawn to the sea, and fascinated by the amazing diversity of form that exists within it. Many marine organisms, with their remarkable (and, sometimes, downright bizarre) adaptations, have arrived at solutions to seemingly intractable biological problems – and if I was being honest, I was just as interested in understanding the skate’s oddities as I was in resolving deeply conserved features that were present at the origin of jawed vertebrates.

So, what’s weird and wonderful about the skate? Hmmmm, flat as a pancake? Electroreceptive? Toothy denticles on the skin? Oviparous mode of reproduction? I’ve always worked on skeletal development, and both my parents suffer from arthritis, and so, in that moment, I pivoted to my go-to organ system – the skeleton – and grasped at three relatively simple observations. The first observation was that cartilaginous fishes (the group of animals that includes sharks, skates and stingrays) do not form bone, but rather (as their name suggests), possess a skeleton that is composed almost entirely of cartilage. This stands in stark contrast to what is seen in mammals: in mammals, cartilage is predominantly an embryonic tissue, and the vast majority of cartilage is replaced by bone, through a process known as endochondral ossification. In adult mammals, cartilage persists in very few places within the skeleton – among them, as the thin pads of articular cartilage that are found within joints. The second observation was that, although cartilage is a rather homogeneous and simple-looking tissue (it only has a single cell type – the chondrocyte – Figure 3), it has very little capacity for spontaneous repair (for example, following articular cartilage damage), and it is surprisingly difficult to engineer in vitro. While much progress has been made in developing cell-based therapies for cartilage repair, many of these approaches are still hindered by the frustrating tendency of in vitro cartilage to differentiate toward a bony fate. The third observation related to the old adage that your pet goldfish will grow to the size of its tank. Of course, this is a gross oversimplification, but it is generally true that, unlike mammals (whose growth curves plateau), many fishes do, indeed, continue to grow (albeit very slowly) in a largely indeterminate manner.

And so, I pondered out loud, if the skate skeleton is composed entirely of cartilage, and if that skeleton exhibits some sort of indeterminate growth, could it be that skates hold, within their skeleton, a mechanism to generate new cartilage in adulthood? And could this mechanism not only allow them to generate new cartilage during normal growth, but perhaps also to repair injured cartilage? There is mounting evidence that the cartilaginous skeleton of sharks and skates is a derived condition – in other words, cartilaginous fishes didn’t primitively lack bone, but rather lost it (for the latest on this topic, see this exciting pre-print by Martin Brazeau, Sam Giles and colleagues). If, through evolution, cartilaginous fishes have come up with a way to make cartilage as a permanent, growing tissue (rather than as an embryonic stepping stone toward bone) – and if they did so from an ancestral bony condition – could studies of cartilage development, growth and repair in skate inform new approaches to cartilage repair in mammals? Needless to say, at this point, my parents were rapt, sold, and ready to get in on the ground level…

While it is absolutely true that my lab’s work on cartilage growth and repair was born from a conversation with my parents, it is an exaggeration to say that this project crystallised and rolled out as smoothly as I set out above… In reality, after that fateful conversation, this project came together very episodically, over nearly 8 years (and mainly as a side project). Below, I’ll briefly run you through some of the major findings of our recent paper on adult chondrogenesis and cartilage repair in the skate (in the order in which they occurred – which, probably unsurprisingly, is not the order in which they appear in the paper…). In many cases, the figures that I’ve included here show more detail than I can succinctly address in the text – so for further information, please do take a look at our paper.

The fin cartilages of adult skates are permeated by canals, containing blood vessels and other cell types

In the 1980’s, it was reported that the vertebral cartilages of some large sharks were permeated by a series of canals (Hoenig and Walsh, 1982, Can. J. Zool. 60: 483-485). This isn’t something that is seen in the embryonic cartilages of other vertebrates (except for the transient invasion of cartilage by canals during endochondral ossification), and so it was speculated that these canals could function in the nourishment, maintenance and growth of cartilage in these sharks during adulthood. We decided to focus our study on the metapterygium (one of the basal fin cartilages) of the skate, as this element is easily recognisable at all life stages, and its location makes it easily accessible for surgical manipulation (Figure 4). We cut sections through the metapterygium of adult skates, and saw that this element is also permeated by cartilage canals. These canals originate in the perichondrium (the fibrous tissue that wraps around the outside of cartilaginous elements), and extend into the core of the metapterygium. In agreement with earlier reports, we found that these canals contained blood vessels as well as a number of other connective tissue-like cell types, and we found that the blind ends of these canals were sites of active deposition of type II collagen (the predominant collagen of cartilage extracellular matrix) (Figure 5). Could the perichondrium be a source of cartilage progenitor cells in adult skates? And could these canals serve as a means of delivering cells and generating new extracellular matrix deep within the cartilage of the metapterygium? Testing for label retaining cells within the adult skate skeleton, and attempting to trace their progeny, would have been a logical next step – and we would eventually get to that – but not before first asking…

Can skates can spontaneously repair injured cartilage?

Why not shoot straight for the moon, right? I was interested in testing whether adult skates could spontaneously repair a cartilage injury that was comparable in scale to a very severe mammalian osteoarthritic lesion. The problem was, I had no money to carry out these experiments (adult skates require a large amount of tank space and care), and no experience working with adult skates. So I decided to apply for a Research Grant from the Fisheries Society of the British Isles (which would just cover the costs of animal care), and after a few failed attempts, I was eventually successful. I also joined forces with then MBL veterinarian, Dr. Amy Hancock-Ronemus, who had a lot of experience with the maintenance and care of adult skates, and who was keen to collaborate on this work. Amy and I developed a biopsy protocol to remove a ~3-4mm wedge of cartilage from the metapterygium of adult skates, and we performed this procedure on twenty-six animals, collecting two animals shortly after the procedure, and then two animals per month for the following year, to assess repair.

Mammalian articular cartilage injuries cannot spontaneously repair – rather, injury sites become filled with scar tissue, or with fibrocartilage, which is mechanically inferior to the hyaline cartilage that typically resides in joints. In skate, we noticed that at 2 months post-operation, the cartilage injury sites that we induced in the metapterygium were completely filled with an undifferentiated connective tissue, and that by 3 months, this tissue began to differentiate into hyaline cartilage. Histologically, this repair cartilage resembled adjacent uninjured cartilage – it contained chondrocytes, and an extracellular matrix composed of type II collagen that was continuous with the matrix of adjacent non-injured cartilage. This repair tissue progressively differentiated from the bottom of the injury site to the top, and by 11-12 months post-operation, the injury sites were completely filled with new cartilage (Figure 6). These observations suggested to us that skates do have the capacity to spontaneously repair injured cartilage, though they didn’t tell us where the repair tissue comes from. However, by chance, a small number of our cartilage biopsies were not completely successful, resulting only in damage to the perichondrium, without removal of a wedge from the underlying cartilage. In these cases, we observed the formation of a large mass of new cartilage between the native cartilage and the perichondrium. This led us to hypothesise that the perichondrium was the source of new cartilage during the skate’s injury repair response, and that mechanical disturbance of the perichondrium, even without the removal of underlying cartilage, was sufficient to trigger the onset of chondrogenesis.

Skates possess label-retaining progenitor cells in their perichondrium, and these cells give rise to new chondrocytes in adults

Label retention experiments have long been used in the fields of cell/developmental biology and regeneration, as a means of testing for the presence of dividing cells (for example, putative progenitor cells) in vivo. Briefly, a label that will become incorporated into newly synthesised DNA is introduced into a system, and this label is then detected and visualised, with retention used as a proxy for cell division. Historically, tritiated thymidine or bromodeoxyuridine (BrdU) has been used for such experiments, though 5-ethynyl-2-deoxyuridine (EdU) has emerged as an increasingly popular alternative because of the relative ease, speed and simplicity of its detection. We conducted an EdU retention experiment in adult skates, with the aim of resolving whether/where cycling cells (i.e. putative progenitor cells) were located within the adult skeleton. We gave adult skates 3 intraperitoneal injections of EdU (with each injection spaced two days apart), and then we tested for the presence of EdU-retaining cells in the metapterygium. We noted that EdU-labeled cells were recovered exclusively within the perichondrium, with no label-retaining cells in the cartilage itself. We also noticed two morphologically distinct populations of EdU-positive cells within the perichondrium – the “outer” perichondral cells, with round nuclei, and the “inner” perichondral cells, which have flattened nuclei, and which sit at the boundary between the perichondrium and the underlying cartilage. These observations suggested to us that cartilage growth in adult skates likely involved a population of progenitor cells within the perichondrium, and wasn’t occurring through continuous proliferation of differentiated chondrocytes.

We reasoned that 1) as cell division was likely quite slow in the skate, 2) as EdU remains detectable in the progeny of labelled cells for several rounds of division, and 3) as label-retaining cells were located only within the perichondrium at the time of injection, we might be able to use this labelling approach to lineage trace these putative perichondral progenitor cells. So we conducted a set of EdU pulse-chase experiments, this time collecting animals at 1, 2, and 5.5 months post-injection – and this is where Aleksandra Marconi joined the project. By this time, I’d left Dalhousie University and started my own group in the Department of Zoology at the University of Cambridge. Aleks is a PhD student on our Wellcome-funded developmental biology PhD programme, and was interested in the problem of post embryonic cartilage growth in the skate. Aleks decided to do a rotation in my lab, and was keen to analyse the adult skate label retention experiments that had been sitting on my shelf for a couple of years. After confirming the presence of EdU-positive cells within the perichondrium of the metapterygium at the time of EdU injection, Aleks found that by 2 months post-injection, she began to see an increase in the number of EdU-positive cells within the perichondrium, and the appearance of EdU-positive cells within the cartilage canals. And by 5.5 months post-injections, she recovered EdU-positive cells within the perichondrium and cartilage canals, as well as EdU-positive chondrocytes at two places within the cartilage of the metapterygium: superficially, beneath the perichondrium, and deeper within the cartilage, adjacent to the blind-end of cartilage canals (Figure 7). These observations led us to propose that the perichondrium of the adult skate metapterygium houses a population of (likely self-renewing) label-retaining progenitor cells, and that these progenitors give rise to new cartilage throughout adulthood via two routes: superficially, by apposition from the perichondrium, and interstitially, via transport of progenitor progeny within cartilage canals.

Skate inner perichondral cells express markers of embryonic chondrogenesis

In parallel with the above experiments, we were also looking at gene expression within the embryonic, juvenile and adult skate skeleton. Around that time, we began studying gene expression by hybridisation chain reaction (HCR) – a simple and sensitive method for multiplexed fluorescent mRNA in situ hybridisation, in any taxon, and with any tissue prep (Choi et al., 2018, Development, 145: dev165753). In mammals, differentiation of mesenchymal cells into chondrocytes is marked by the expression of Col2a1 (the gene encoding type II collagen), and Col2a1 is directly transcriptionally regulated by the SoxE and SoxD-class transcription factors Sox9 and Sox5/6. We found that, as in mammals, embryonic chondrocytes in the skate co-expressed Col2a1, Sox9, Sox5 and Sox6, pointing to the likely conservation of this cartilage gene regulatory mechanism across jawed vertebrates (Figure 8). Additionally, within the juvenile and adult skeletons, we found that Col2a1, Sox9, Sox5 and Sox6 were predominantly expressed in the periphery of the cartilage (consistent with our model of appositional growth, and the birth of new chondrocytes around the periphery of the metapterygium), and we noticed that the morphologically distinct “inner perichondral cells” (i.e. the flattened cells that sit at the boundary between the perichondrium and underlying cartilage, and that were identified as putative progenitor cells in our label retention experiments) express Sox9, Sox5 and Sox6, but not Col2a1 (Figure 9). This is consistent with the hypothesis that these cells have chondrogenic potential, but have not yet differentiated into chondrocytes.

We therefore propose that post-embryonic growth of cartilage in the skate occurs by the slow-but-steady development of new chondrocytes from a population of perichondral progenitor cells, and that these progenitor cells are recognisable, transcriptionally, by their expression of the pro-chondrogenic transcription factors Sox9, Sox5 and Sox6. We also show that the persistent presence of perichondral progenitor cells in adult skates correlates with an ability to spontaneously repair injured cartilage. We think that these are really exciting findings, though, of course, there are still a number of outstanding questions: Is the perichondrium homogeneous in its chondrogenic potential? Or, is there a specialised subpopulation of perichondral chondroprogenitor cells? To what extent is the endochondral ossification transcriptional programme conserved in cartilaginous fishes? And where does this programme arrest to permit the persistence of cartilage as a permanent skeletal tissue? Our work toward answering these questions is ongoing, and we look forward to sharing more of our progress with the developmental biology and regeneration community shortly.

So, what started off as a side project, inspired by a conversation with my parents and supported initially by a small society grant, has now become a major new line of research in my lab, and has renewed my curiosity in (and enthusiasm for) the bizarre little skate that I started working on as a graduate student fifteen years ago. Moreover, I think that this project illustrates a point that is made most eloquently by a quote attributed to the former MBL scientist, Nobel laureate Albert Szent-Gyorgi (and that is emblazoned on the wall leading into the tank room at the MBL Marine Resources Centre): “Research is to see what everybody else has seen and think what nobody has thought”. This research project stemmed from three observations – none of which were particularly novel or profound (or even our own to begin with!). But by digging a little deeper and conducting a few simple experiments, we were nevertheless able to learn something new and exciting about the unique skeletal biology of cartilaginous fishes.

As a side note: in 2021, my lab will be relocating to the Marine Biological Laboratory in Woods Hole, where I will be taking up a resident scientist position. I am very excited about this move, not least because it will allow us to develop the skate even further as a model system for developmental biology and regeneration. And I recently learned from my friend, colleague and fellow Woods Hole enthusiast, historian of science Shane Jinson, that the lab space we are moving into in the Lillie Building once belonged to, of all people, Albert Szent-Gyorgi (Figure 10)!

(3 votes)

Loading...

I started off as quite little—just one cell, in fact. No heart, no brain, no blood flowed in me and yet, somehow I found the motivation in me to divide. One me made two and two mes made four, till many tiny mes made me a full-fledged embryo with a heart full of hope. As I grew older, my heart grew with me. My body and heart needed to synchronize their growths, you see, because if my heart grew slower, then it would pump less blood into my system, and my other organs that needed blood to grow would not be able to do so properly. This posed a challenge for me– how do I make sure that my body knows my vessels are growing, and my vessels know my heart is growing? Please don’t tell me that’s yet another thing my brain has to manage. Wait, do I even have a brain yet!?

Anyway, perhaps it’s easiest if I use some intrinsic property of my blood, the fluid that connects my body and vessels and heart, to transport this important message. This way, as my heart beats faster and more blood flows through my system, my vessels will take the hint and grow accordingly. Going back to connections, let me first focus on my outflow tract, which connects my heart to my aortic vasculature. Perhaps if I tell my outflow tract to widen as blood flow and contractility increase, it will maintain my blood pressure while also allowing information in blood to pass through to my other systems. Ugh, so how I do that?

Hmm. What if the cells in the inner endothelial lining of my outflow tract respond to blood flow and contractility by dividing? What if they accumulate cells from the neighboring vessels, in conjunction with neighboring vessels accumulating them from more distal vessels? Maybe I’ll do both—yes, that sounds like a good strategy. But how do I regulate this growth? Maybe I should have many opposing signals, reacting to multiple inputs, towards the unified goal of getting the outflow tract to a particular lumen size at a particular developmental stage. I’m feeling lazy, I’ll just repurpose my good ol’ TGFb pathway to do this—put some receptors in my endothelial cells and have my blood carry physical and molecular cues to activate them.

Great, I think I have a functioning cardiovascular system! And it’s caught in this self-regulating loop where function informs form, which feeds back to function. I feel so smart! Kudos to me figuring this out over evolution. Well, I guess I’ll give an additional kudos to this grad student who figured it out in 5 years.

I still believe I’m the smarter one. But if you really want to read what she did, here’s the link to her paper: https://dev.biologists.org/content/147/12/dev185900

<3 <3

(9 votes)

Loading...

Dear All

We are looking forward to an exciting UK SouthWest Zebrafish Meeting at the 11 Sep 2020!

If you have not already, register and also submit your abstracts for either talks or posters. Talks and posters will be given to students, early career researchers and technicians. Our deadline for abstract submission is Friday 24th July, so submit your abstracts on our website: https://swzm2020.wixsite.com/swzm2020/registration. On the website you will find the online registration form, as well as the abstract form to fill out and upload.

Virtual Meeting:

We have been working behind the scenes to build our virtual meeting! We are planning to hold the meeting via a central hub on Padlet.com. This means we can host an online poster exhibition, secure to all delegates, where you will be able to browse and read posters, leave comments and interact with presenters and crucially vote for ‘best poster’! Prizes will be awarded for best talks and posters! We will also use Zoom to host our series of talks, break-out sessions, talks from sponsors, as well as an online ‘Zebrafish Zoom Café’ for breaks and general discussion. More details to come!

New Sponsors:

Good news! We can now confirm our meeting will be free from any registration fees for delegates. We can now confirm we have been kindly sponsored by The Company of Biologists, through a Scientific Meeting Grant, so we can waive registration fees. We can also announce we are kindly sponsored by Tecniplast and DanioLabs.

Special Issue:

We would like to announce that a Special Issue of ‘Histochemistry and Cell Biology’ focussing on ‘In vivo cell biology in zebrafish’ will accompany the meeting. Please email us for further details. We are looking forward to hearing from you with research!

Please pass this information on to anyone you think may be interested and feel free to tweet about the event using #SWZM20 and follow us on Twitter @Swzm20!

Looking forward to hearing from you all,

Steffen, Lucy, Holly, Michael, Josh, Chengting & Yosuke
(South West Zebrafish Organising Committee)

(No Ratings Yet)

Loading...

In this episode of Genetics Unzipped, Kat Arney tells the stories of two women – one a scientist fascinated by dancing mice, the other a seamstress with a deadly family legacy – who made significant contributions to our understanding of cancer as a disease driven by genetic changes, paving the way for lifesaving screening programmes for families.

Kat’s upcoming new book Rebel Cell: Cancer, Evolution and the Science of Life, explores what we’ve learned so far about where cancer comes from, where it’s going, and how we might finally beat it. It’s coming out in the UK on the 6th of August and in the US on the 29th September – and is available now to pre-order from Amazon or your retailer of choice.

While she was researching the book, Kat came across the stories of two remarkable women who both made significant contributions to our fundamental understanding of cancer, but who have tended to be overlooked in many tellings of the history of cancer research. Here are their stories.

Born in Minnesota in 1879, Maud Slye was a cancer pathologist who dedicated her career to studying patterns of cancer inheritance in more than 150,000 mice. But as well as being a dedicated scientist (as well as a part-time poet), her ideas about eugenics brought controversy.

Even so, Slye’s work earned her a gold medal from the American Medical Society in 1914 and from the American Radiological Association in 1922. She was also awarded the Ricketts Prize from the University of Chicago in 1915 and an honorary doctorate from Brown University in 1937. She was even nominated for a Nobel prize in 1923.

Running parallel to Slye’s work in mice was the research carried out by Aldred Warthin, a doctor working at the University of Michigan in Ann Arbor. One day in 1895, a chance meeting between Warthin and a local seamstress, Pauline Gross, set the two of them off on a 25-year-long quest to understand why so many members of Pauline’s family had died from cancer at a young age.

Pauline spent years compiling detailed family histories, enabling Warthin to trace the pattern of inheritance through Family G, as it became known. Like Slye, Warthin was a fan of eugenic ideas,  and his work fell out of favour after his death. Pauline’s detailed genealogy lay undisturbed in a closet in the university until the 1960s, when American doctor Henry Lynch and social worker Anne Krush rediscovered her work and continued extending and investigating Family G. Today, members of Family G – and others around the world carrying dangerous variants in mismatch repair genes – can undergo genetic testing, with a range of preventative and screening options available.

The story of Pauline and Family G, and the impact that their genetic legacy has had on the family down the generations, is beautifully told in the book Daughter of Family G, a memoir by Ami McKay.

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

Subscribe from Apple podcasts/iTunes, Spotify and all good podcast apps to make sure you get the latest episodes and catch up on our 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

(No Ratings Yet)

Loading...

By Héloïse Dufour, Shigeyuki Koshikawa and Cédric Finet

In this post we will discuss our recent paper entitled “Temporal flexibility of gene regulatory network underlies a novel wing pattern in flies” [1]. We initiated the present project in Sean Carroll’s lab where the pigmentation in drosophilids was used as a model to study evolutionary genetics. When we started back in 2010, we knew that the black dots on Drosophila guttifera wings result from the co-option of the protein Wingless during evolution [2]. However, D. guttifera does represent a particular case: the black dots on the wing are associated with campaniform sensilla, which is not the case for other wing colour patterns in drosophilids. The most vivid examples of wing pigmentation patterns are found among the Hawaiian flies, from simple pigmentation around the veins to complex black and white patterns [3], but we were aware that the Hawaiian flies are hardly tractable in the lab. In the meantime, we came across the species Samoaia leonensis which was maintained at the National Drosophila Species Stock Center. We decided to investigate the making of the wing colour pattern in this species.

The genus Samoaia: a case study of pigmentation and its evolution

Samoaia is a small genus of seven described species endemic to the Samoan Islands in the central South Pacific. For example, the main model of our study S. leonensis exhibits a beautiful and complex black and white spot pattern on its wings (Figure 1). This species is a perfect case of pattern matching, with white spots not only covering the black wings, but the legs, the head, the abdomen, and the notum as well. [For etymology lovers, it is tempting to see in leonensis a reference to the lion, then to the jaguar and its spotted fur. Well, entomology systematics can be sometimes down-to-earth: the species S. leonensis was simply discovered around Leone on Tutuila Island.]

The entire genus Samoaia is an excellent model to study the evolution of pigmentation, especially the modularity of pigmentation. The species S. attenuata has indeed white spots on the legs only (Figure 1), suggesting that the whole body ‘camouflage’ of S. leonensis might result from the stepwise gain of spots in different organs during the course of evolution.

Key finding nº 1

We showed that the co-option of the transcription factor Engrailed underlies the making of the white wing spots in S. leonensis wings. Whereas the expression of Engrailed is restricted to the posterior wing compartment in early pupal stages, its expression becomes spotty in both anterior and posterior compartments in later stages. This result is a big surprise for Drosophila developmental biologists for whom engrailed is the posterior identity gene by definition. Would it mean that there is a critical point beyond which engrailed is no longer required for AP patterning?

We tested this hypothesis in D. melanogaster. We silenced or overexpressed engrailed specifically in the wing at different time points. We were able to precisely define three different time windows during which (i) disturbing engrailed expression results in severe morphological defects, (ii) disturbing engrailed results in minor vein defects, (iii) disturbing engrailed expression does not lead to visible phenotype. We argue that the co-option of a given gene is possible beyond its corresponding critical point.

Key finding nº 2

We found that the co-option of Engrailed in the S. leonensis wing is partially independent from the other genes of the AP specification network. For instance, hedgehog and engrailed are not co-expressed in the anlagen of the future white spots, whereas these two genes are co-expressed in the posterior wing disc. Would it mean that the interactions between players of the AP specification network are labile over development? Is it a specificity of S. leonensis late development?

Again, we tested this hypothesis in D. melanogaster. In the D. melanogaster wing disc, Engrailed acts in coordination with other players of the anterior-posterior (AP) specification network. For example, Engrailed both activates the expression of Hedgehog and represses Cubitus interruptus in the posterior compartment. We found that the AP network is only partially maintained in late pupal stages in D. melanogaster. For instance, the depletion of engrailed transcripts in the developing late pupal wing no longer causes the expansion of Cubitus interruptus expression into the posterior compartment. Our results suggest that the temporal flexibility of regulatory gene networks might facilitate gene co-option during evolution.

Key finding nº 3

We further investigated the function of several genes of the AP specification network over wing development in D. melanogaster. Except for cubitus interruptus and hedgehog that behave in a similar way, we found that every single gene of the gene regulatory network has its own functional time window. This property might facilitate the co-option of a single gene independently from the whole gene network. We followed the same approach for supplementary genes, and found that wingless and Distal-less have a critical time point particularly early. Wingless and Distal-less have been co-opted to generate wing pigmentation in D. guttifera [2] and D. biarmipes [4], respectively. We propose that genes with an early critical point might be more easily co-opted during evolution.

A perfect model but…

The only fly in the ointment is the suitability of Samoaia flies for functional developmental biology. Let us now share a little bit of the unsaid B-side of the project. We injected S. leonensis embryos for two years and finally obtained a single transgenic line that turned to be useless on its own. The members of the Carroll lab wondered how it was possible to accumulate so many impediments. The “curse of Samoa has struck again” became quickly the new leitmotiv in the lab. It may be useful for the community to know a few of the technical challenges. First, the chorion of S. leonensis embryo is very thick and hard. After the first attempts, the injection post was scattered with dozens of broken needles like the French lines after the battle of Waterloo. We therefore dechorionated the embryos by bleaching prior to microinjection, and let them hatch in halocarbon oil to prevent them from desiccation. The larvae looked pretty healthy but 90% of them died within the next few days. After one year of laborious work we finally got transgenics carrying the transgene UAS-engrailed. Believe us, GFP never appeared so beautiful and ecstatic. We were halfway and Christmas was almost there. Such a gift! For us the coming new year meant more and more injections. Again, we encountered numerous issues and got a single transgenic larva carrying the transgene nab-Gal4. The larva died, bringing away our last hope of seeing a pigmentation phenotype in S. leonensis.

Fly wing coloration: future directions

The Samoan Islands and their colorful flies would have been a real change of scene. But the call of the genetics is too strong, we need tractable species… Back to the real world, we wonder what mystery is still unsolved in the pigmentation patterns of flies [5]. Many genes are probably involved in the pattern formation, and many of them still await discovery [6]. We have to clarify how the coordinated regulation of many genes was acquired to make novel pigmentation patterns, and how pre-existing gene regulatory networks were (or not) modified and recruited. In addition to the on/off regulation of gene expression, the transport of signaling molecules, hormones and precursors of pigments could be also key factors for pigmentation evolution. Besides pigmentation, the structural coloration of membranous wings region has been proposed to be play a role in visual communication. Little is known about how the wing structural coloration is formed during development and how it evolved. Fly wing coloration has many chapters, some still being written as time flies…

References:

[1] Dufour HD, Koshikawa S, Finet C. (2020). Temporal flexibility of gene regulatory network underlies a novel wing pattern in flies. PNAS 117: 11589-11596.

[2] Werner T*, Koshikawa S*, Williams TM, Carroll SB. (2010). Generation of a novel wing colour pattern by the Wingless morphogen. Nature 464: 1143-1148.

[3] Edwards KA, Doescher LT, Kaneshiro KY, Yamamoto D. (2007) A database of wing diversity in the Hawaiian Drosophila. PLoS ONE 2(5): e487.

[4] Arnoult L*, Su KF*, Manoel D*, Minervino C, Magriña J, Gompel N, Prud’homme B. (2013). Emergence and diversification of fly pigmentation through evolution of a gene regulatory module. Science 339: 1423-1426.

[5] Koshikawa S. (2020). Evolution of wing pigmentation in Drosophila: diversity, physiological regulation, and cis-regulatory evolution. Development, Growth & Differentiation (in press).

[6] Fukutomi Y, Kondo S, Toyoda A, Shigenobu S, Koshikawa S. (2020). Transcriptome analysis reveals wingless regulates neural development and signaling genes in the region of wing pigmentation of a polka‐dotted fruit fly. The FEBS Journal (in press).

(2 votes)

Loading...

Location:  Highfield Campus
Salary:   £30,942 to £36,914 per annum 
Full Time – Fixed Term until 31/01/2022
Closing Date:  Thursday 25 June 2020
Interview Date:  Wednesday 01 July 2020
Reference:  1266420BJ

A Research Fellow position is available in Dr. Salah Elias laboratory at the School of Biological Science (SoBS) – University of Southampton (UoS), to study the mechanisms of asymmetric cell division during mammary gland development and homeostasis. The position is available until 31/01/2022 in the first instance.

The Project

Our lab focusses on studying the mechanisms that regulate mammary stem cell fate and dynamics in normal development and breast cancer. This exciting project is a collaboration between our group and Dr. Philip Greulich group based at the School of Mathematics at UoS. It will employ combined in vivo lineage tracing, quantitative three-dimensional (3D) high-resolution imaging and next generation sequencing as well as mathematical/computational modelling to identify novel mechanisms that control mitotic spindle orientation in mammary stem cells; and determine how these mechanisms influence cell fate outcomes.

The Successful Candidate

We are looking for a creative, ambitious and skilled Postdoctoral Researcher Scientist willing to challenge an innovative project by adopting a pro-active attitude and an analytical approach, with a strong interest in interdisciplinary collaboration.

You will be responsible for the development of the wet-lab part of the project, which includes experimental design, data collection and interpretation. You are also expected to contribute to new ideas for research projects, develop ideas for writing grant proposals, prepare scientific reports, write up results for publication in international peer-reviewed journals.

You will hold a PhD* or equivalent professional qualifications and experience in stem cell and/or developmental biology (or related field). A strong evidence of proficiency in cell biology and quantitative advanced microscopy in vivo is necessary. Experience in Next Generation Sequencing is desirable.

The Environment 

There is a strong interdisciplinary research focus at SoBS bringing together researchers from Biological and Medical Sciences, Computer Sciences, Physics and Mathematical Sciences with experimental work housed in a £45 million building that encompasses cutting-edge research infrastructures. You will have full access to all resources and undertake appropriate training in the use of the equipment of our state-of-the-art core facilities to accomplish your studies. You will thrive within a unique international, stimulating and challenging environment.

For informal enquiries, please contact Dr Salah Elias S.K.Elias@soton.ac.uk and/or Dr. Philip Greulich P.S.Greulich@soton.ac.uk

Given COVID-19 outbreak, virtual interviews will be held using Microsoft Teams or Skype.

Equal Opportunities

SoBS holds an Athena SWAN Silver Award, demonstrating commitment to equal opportunities and gender balance in the workplace.

Application Procedure

You should submit your completed application form online at www.jobs.soton.ac.uk. Please include (1) a cover letter outlining your scientific interests, describing how you meet the requirements of the position, and an outline of future goals; (2) a curriculum vitae, (3) contact information for at least two references.

If you need any assistance, please contact Hannah Farrance (Recruitment Team) on recruitment@southampton.ac.uk . Please quote vacancy reference number 1266420BJ on all correspondence.

*Applications will be considered from candidates who are working towards or nearing completion of a relevant PhD qualification. The title of Research Fellow will be applied upon successful completion of the PhD. Prior to the qualification being awarded the title of Senior Research Assistant will be given.

(No Ratings Yet)

Loading...

The Company of Biologists Workshops provide leading experts and early-career researchers from a diverse range of scientific backgrounds with a stimulating environment for the cross-fertilisation of interdisciplinary ideas. The programmes are carefully developed and are intended to champion the novel techniques and innovations that will underpin important scientific advances.

The Workshops really are fantastic events, but don’t just take our word for it – read Node pieces from participants of recent Workshops on birth defects, the choroid plexus and cerebrospinal fluid biology, chromatin in development, chromatin and evolution, the human neocortex, in vitro neural differentiation, intercellular interactions, and also check out these two Development Spotlight articles that arose from Workshops.

While the 2019 Workshops have been postponed due to the COVID-19 pandemic, we hope to be running our scheduled events from January 2021 onwards. We’re also looking ahead to 2022: we are currently seeking Workshop proposals.

Workshop proposals should take into account the following:

• The focus should be on cutting-edge scientific research in topic areas that are novel and not covered by traditional conferences.
• Proposals that concentrate on emerging or cross-disciplinary themes are particularly encouraged.
• Organisers should be experts in their field, or have sufficient standing to attract world-class speakers and attendees.
• Particularly strong postdoc and early-career researcher applications will be considered.
• An indication of how the Workshop will contribute to establishing new collaborations or research directions should be provided.
• Each Workshop will consist of 30 delegates including 20 speakers and 10 early-career researchers (places to be applied for). Proposers should ensure maximum diversity in the proposed attendee list.

The next deadline for applications is 31 July 2020 – apply here.

(No Ratings Yet)

Loading...

Exploring the contribution of lymphatics towards diabetic kidney disease and their potential as a therapeutic target

A 3-year PhD Studentship funded by Diabetes UK is available within the Kidney Development and Disease Group (http://www.ucl.ac.uk/ich/research/developmental-biology-cancer/developmental-biology-birth-defects/kidney-development-and-disease-group) in the Developmental Biology and Cancer Programme, Great Ormond Street UCL Institute of Child Health. The studentship will commence in October 2020 under the supervision of Dr David Long and Professor Luigi Gnudi (King’s College London).

The aim of the studentship is to examine how lymphatic vessels contribute to diabetic kidney disease and their potential as a therapeutic target. The student will (i) use three-dimensional imaging technologies to study the lymphatics of diabetic kidneys down to the detail of single cells; (ii) isolate cells from diabetic kidneys and perform single cell RNA sequencing to see how gene expression changes in lymphatics on a cell-by-cell basis, and how lymphatics might be interacting with other cells in the diseased kidney and (iii) target kidney lymphatics using gene therapy; delivering VEGF-C, a lymphatic growth factor, to the diabetic kidney. The project will utilise multiple techniques ranging from animal husbandry, three-dimensional imaging technologies, flow cytometry, single cell RNA-sequencing and gene therapy strategies.

For a full project description please see the GOS ICH website: https://www.ucl.ac.uk/child-health/phd-studentship-kidney-research

Applicants should have, or expect to receive an upper second-class Bachelor’s degree and a Master’s degree (or equivalent work experience) in a relevant discipline or an overseas qualification of an equivalent standard. The student will receive a starting stipend of £19,000 per annum (including London weighting) as well as the cost of tuition fees for UK/EU students (applicants from non-EU countries can apply but will have to personally fund the difference between the home/EU rate and the overseas rate).

To apply, please send a current CV including the contact details of two professional referees as well as a cover letter to ich.dbc.admin@ucl.ac.uk.

Enquiries regarding the post can be made to Dr David Long (d.long@ucl.ac.uk).

Deadline for receipt of applications: 19th June 2020, 5pm

Interview date: TBC

(No Ratings Yet)

Loading...

The Alenius lab has a fully funded postdoc position opening at at Umeå university, Sweden. Our group combines Drosophila  and mouse genetics to investigate the fundamental mechanisms that control neuronal activity. We are shifting gears for this project and the focus is to identify hormones that regulate taste and olfaction in Drosophila.

We seek an enthusiastic, highly motivated candidate with a strong background in either Drosophila molecular biology or cell signalling. The position involves exploring candidate hormones from a screen using state of the art Drosophila genomic tools, behaviour analyses and biochemistry. Thus, additional skills in Drosophila neuroscience, imaging, and behavior analysis are considered a plus.

Candidates are encouraged to send applications (cover letter, CV, and contact information of 3 references) to the link below. Application deadline is June 23, 2020.  Reviewing of applications will start immediately until the position is filled. Openings are available immediately. If you have questions do not hesitate to write: mattias.alenius@umu.se

Use this link to apply: https://umu.varbi.com/en/?jobtoken=1cd2fd52e7a1e1dc6ae07e1cc2602f2d469ad26d5

(No Ratings Yet)

Loading...