Lab sizes vary considerably, from small groups that include only the lab head and maybe a student or postdoc, to huge enterprises of several dozen people, including senior postdocs that manage smaller sub-groups under the overall supervision of the PI. What are the advantages of small versus large labs? Is it inevitable that a lab must continuously increase in size to be competitive? In other words:

How big should a lab be?

Share your thoughts by leaving a comment below! You can comment anonymously if you prefer. We are also collating answers on social media via this Storify. And if you have any ideas for future questions please drop us an email!

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Nature’s most interesting secrets can sometimes be found in our own backyards. One such secret is related to all birds, those pigeons, thrushes and sparrows that we see everyday. This familiarity means that we do not think too much of birds passing them by on our way to work or school. However, if the birds no longer existed, wiped out by an ancient cataclysm, and were only known to us through their fossil remains, we would be truly awed by them, by their strange anatomy, by how different they would appear from all other vertebrates, including their own ancestors. Modern birds are the remaining descendants of once glorious lineage of theropod dinosaurs, the bipedal carnivorous reptiles who dominated the landscape during the Mesozoic Era. The theropods had long and powerful snouts with many teeth, relatively small eyes and brains – a far cry from modern birds that have no teeth, their skulls featuring relatively large eyes and brains. Instead of a face with a snout constructed from many bones, birds have an elongated bill, composed largely of just two bones – one bone of the upper beak (premaxillary bone) and one for the lower jaw (mandibular bone). The beaked face of the modern bird looks distinctly different from the faces of their ancestors. How and why the birds acquired their unique craniofacial appearance?

In 2012 my group published Bhullar et al., 2012 report where we explained the first part of the story of the avian skull and face [1]. We studied skulls of the modern and primitive birds, non-avian theropod dinosaurs and other members of the Archosauria, a group of amniotes, which originated about 250 million years ago and included crocodilians, pterosaurs, all dinosaurs and birds. Landmarks were placed on each skull at homologous positions that allowed us to compare archosaurian skull shapes as they evolved and changed over millennia. We used computer software-based geometric morphometric and principal component (PCA) analyses (Fig.1). To better understand the role of developmental changes in this evolutionary story, we also included late embryos and juveniles of both birds and dinosaurs, where available. First, we noticed that the skulls of adult theropods became longer as they evolved from the more basal archosaurs. Second, the skulls of the theropod embryos and juveniles were morphologically different from adults occupying a distinct area of morphospace – they had shorter faces, fewer teeth and proportionally larger brains and eyes. Lastly, the first birds, such as the famed Archeopteryx and Confuciusornis were found precisely in the theropod “baby space”. Ontogenetically, the early birds appear to undergo little change from juvenile to adult states. For example, the skull of the young Eichstätt specimen of Archaeopteryx is about half size of the Berlin specimen’s skull but has a nearly identical cranial morphology, and, importantly, both of them resemble the juvenile theropod skulls. Thus, we concluded that birds are paedomorphic in terms of their cranial morphology in retaining a morphology as adults that resembles that of the juveniles or embryos of their ancestors. Birds are dinosaurs, whose heads and faces never grow old…

Figure 1. A complicated trajectory of skull shape changes during evolution of non-avian archosaurs and birds. Note the collapse of the face (light grey) and subsequent expansion of the beak 9dark grey) in birds. Euparkeria is an early archosaur, Herrerasaurus is one of the one of the earliest dinosaurs. Guanlong is Guanlong is a tyrannosauroid theropod dinosaur. Archeopteryx is the first bird. Confuciusornis is another early bird. Yixianornis is a beaked bird from the early Cretaceous period. Dromaius (emu) is a basal modern bird [1].

Paedomorphosis is an example of heterochrony, a change in timing or order of developmental events that produces a phenotypic alteration in the adult. There are two ways by which paedomorphosis can arise [2]. One is called neoteny (juvenilization), when somatic development of an animal is slowed or delayed so at the onset of sexual maturity it still retains juvenile characteristics. One of the best-known examples of neoteny is certain species of urodele amphibians, which sexually mature despite preserving a number of larval features, such as a finned tail and external gills. The second type of paedomorphosis is called progenesis when sexual development occurs faster than in the ancestral lineage and results in early somatic maturation and juvenile-looking adults. Paedomorphosis in the bird lineage is probably one of the most striking examples of progenesis reported to date. Our PCA graph shows that birds have significantly shorter ontogenetic trajectories than in all other studied archosaurs. Importantly, these short trajectories also match histological data indicating that sexual and somatic maturation times were truncated during the paedomorphic transformation. So, developmental program in birds is much shorter because they become mature much faster (up to 20 times faster!) than more basal archosaurs.

There was a point in early avian evolution when the shapes of their skulls were nearly perfectly pedomorphic. The modern birds, however, look substantially different from those first birds. Archeopteryx, famously, still had a snout with teeth and, while baby-like, it still looked like a dinosaur with wings. Modern birds have a beak and our latest publication sheds light on how this unique structure evolved from a snout [6]. Modern birds number about 10,000 species, the largest and arguable most successful group of land vertebrates [3]. Much of their success can be attributed to variation in beak shape. Birds use beaks of a bewildering variety of different designs to obtain food items (hooked beaks of predatory birds, long and straight beaks of herons and hummingbirds, deep beaks of finches and sparrows, serrated beaks of mergansers and flamingos for catching fish and filter feeding, respectively), to build or weave nests (most birds), to dig burrows in the ground (puffins and swallows), to hammer or excavate wood to build a hollow enclosure (woodpeckers and chickadees), to dissipate heat (toucans) and to communicate (song birds, storks, owls). Above all, the bird beak is a precision grasping tool, and its exact shape is often critical to its function. In fact, it is likely that bird beaks evolved to replace the long and agile fingers of their theropod predecessors. It is also a great example of a key evolutionary innovation, a novelty that had dramatic phylogenetic consequences [4]. But how the bird beaks originate?

Figure 2. Amniote phylogeny with skull μCT scans and configuration of the premaxillary (red) and maxillary (green) bones. Mammals (Mammalia), lizards (Lepidosauria), and alligators (Crocodylia) all have paired, small and rounded premaxillary bones. Modern birds have fused, large and elongate premaxillae [6].

The upper beak in birds is a particular challenge to understand. It is a novel structure, which forms as a result of rostral expansion of the fused premaxillary bone, which grows as two small capping elements in basal archosaurs and most dinosaurs but expands to structurally and functionally dominate the upper face in modern bird lineage (Fig.2). The remainder of the snout and much of the face in birds are paedomorphically truncated. To address the origin of the avian beak, my group implemented the following research program, developed for studying developmental mechanisms for evolutionary novelties [5]: first, we traced the transformation of the distinctive avian facial skeleton in the fossil record using geometric morphometrics; then we examined candidate gene expression domains in reptiles and birds to phylogenetically polarize expression patterns, and, lastly, experimentally restored the inferred ancestral craniofacial expression patterns in developing chicken embryos [6]. To analyze the results of functional experiments, we included the resultant cranial phenotypes in the broader geometric morphometric analysis, which contained ancestral snouted and bird-faced fossil forms.

Figure 3. Results if functional experiments reveal roles of FGF and WNT signaling in the origin of modern bird beak. μCT scans of alligator skulls, wild- type chick, and FGF inhibitor-treated chick embryonic skulls. Note the large and paired pmx in the inhibitor-treated embryo (stars). Suppression of FGF signaling causes a range of phenotypes including a suppression of medial WNT signaling and completely separated and round pmx bones [6]. 

The principal-component analysis of shape variation in premaxilla of a range of extant and extinct archosaurs (including embryos, juveniles, and adults) revealed that adult and embryonic modern birds were separated from the ancestral forms along in having relatively long, narrow premaxillae and straight-edged premaxillae. Predictably, premaxillae of the first bird Archeopteryx clusters with the non-avian snouted dinosaurs. Next, we determined that the early medial expression of Fgf8 and later medial WNT signaling in the developing faces is phylogenetically exclusive to birds. These molecules are expressed in the right time and the right place to control the formation of snout and beak. Embryos of all other amniotes studied (mouse, turtle, lizard, alligator) had only two lateral expression domains around the nasal pits. We then placed silica bids soaked with either FGF or WNT specific inhibitors to replicate an inferred ancestral pattern. Near-hatching skeletal phenxotypes of both FGF-inhibited and WNT-inhibited experimental embryos were not simply abnormal – they were similar to each other and strikingly resembled ancestral archosaurian forms in having abbreviated, rounded, and partially or fully paired premaxillae (Fig.3). Embryos with strong phenotypes displayed complete separation of the premaxillae with a suture-like division between them. We did not find any evidence of cell death playing a role in generating this atavistic phenotype and instead found evidence for a loss of the fusion zone between the two premaxillae. Interestingly, In addition to the premaxillary bone phenotype, the palates of experimental embryos also showed an altered and more ancestral phenotype. The palatine bones of modern birds have a distinctive shape that allows for a kinetic movement of the upper beak relative to the skull while it fuses broadly with the facial bones and cranial base in other archosaurs.

Figure 4. Comparative analysis of premaxillary shapes in experimental embryos with those from modern birds, primitive birds and non-avian archosaurs. Control embryos and experimental embryos showing near normal phenotypes clustered with forms possessing an avian beak (blue polygon), all of the embryos with the more pronounced phenotypes (red polygon) fell outside of the cluster of beaked birds and most of them instead clustered with more basal archosaurs (grey polygon), suggesting that the ancestral bone shapes were indeed successfully resurrected [6].

This study offers an example how we can probe the intrinsic mechanisms for even large-scale evolutionary transformations. The precise genetic/genomic nature of the regulatory change in expression of Fgf8 remains to be investigated but its implications for both development and evolution of birds are clear and profound. Other molecules and pathways are likely to be involved to explain the full scope o the transformation of the reptilian skull and snout into an avian face and beak. Curiously, we have shown that while the fossil record can provide useful developmental hypotheses, the intermediate phenotypes resulting from our experimental restoration of the inferred ancestral developmental patterns in return predict undiscovered transitional morphologies in the fossil record, yet undiscovered avian ancestors with gap-bridging facial bone phenotypes (Fig.4). It may also be significant that two of the most important modern bird beak bones (pmx and palatine) are regulated by the same pathways and are, thus, integrated developmentally and evolutionarily.

References:

 
Bhullar, B., Marugán-Lobón, J., Racimo, F., Bever, G., Rowe, T., Norell, M., & Abzhanov, A. (2012). Birds have paedomorphic dinosaur skulls Nature, 487 (7406), 223-226 DOI: 10.1038/nature11146

Alberch,P., Gould,S.J., Oster,G.F., & Wake,D.B. (1979). Size and shape in ontogeny and phylogeny Paleobiology , 5, 296-317

Gill, F. B. Ornithology. Freeman, 2006

Hodges, S., & Arnold, M. (1995). Spurring Plant Diversification: Are Floral Nectar Spurs a Key Innovation? Proceedings of the Royal Society B: Biological Sciences, 262 (1365), 343-348 DOI: 10.1098/rspb.1995.0215

Mallarino, R., & Abzhanov, A. (2012). Paths Less Traveled: Evo-Devo Approaches to Investigating Animal Morphological Evolution Annual Review of Cell and Developmental Biology, 28 (1), 743-763 DOI: 10.1146/annurev-cellbio-101011-155732

Bhullar, B., Morris, Z., Sefton, E., Tok, A., Tokita, M., Namkoong, B., Camacho, J., Burnham, D., & Abzhanov, A. (2015). A molecular mechanism for the origin of a key evolutionary innovation, the bird beak and palate, revealed by an integrative approach to major transitions in vertebrate history Evolution DOI: 10.1111/evo.12684

(10 votes)

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This Spotlight article was written by Elizabeth Graham, Julie Moss, Nick Burton, Chris Armit, Lorna Richardson and Richard Baldock, and was first published in Development.

The Atlas of Mouse Development by Professor Mathew Kaufman is an essential text for understanding mouse developmental anatomy. This definitive and authoritative atlas is still in production and is essential for any biologist working with the mouse embryo, although the last revision dates back to 1994. Here, we announce the eHistology online resource that provides free access to high resolution colour images digitized from the original histological sections (www.emouseatlas.org/emap/eHistology/index.php) used by Kaufman for the Atlas. The images are provided with the original annotations and plate numbering of the paper atlas and enable viewing the material to cellular resolution.

The atlas of mouse development

The Atlas of Mouse Development by Professor Mathew Kaufman (Kaufman, 1994) is the de facto standard atlas describing mouse developmental anatomy at the histological level. It set the standard for other atlases that followed and is unmatched in terms of authority and detail. It is an essential volume for all research into mammalian development and remains in high demand without revision since 1994. To build the breadth of understanding of mouse development required for this atlas, Kaufman amassed a major histological slide collection. This comprised multiple fully serial sectioned embryos per stage with the best matching Theiler’s staging criteria selected for image capture. All the original histological slides stained with Haematoxylin and Eosin are carefully archived and indexed, and represent an untapped resource of new material. For each of the embryos selected for annotation, Kaufman chose a series of sections to be photographed, mounted on board and hand annotated using Letraset, then re-photographed to produce the figures reproduced in the printed volume. Fig. 1 shows an example of a plate that was never published. The Atlas has 980 section images with about 12,275 annotations – a truly painstaking process showing an uncompromising dedication to science.

Fig. 1. An example of the original artwork for the Atlas of Mouse Development. This plate was never published and shows the Letraset lines and numbers pasted on top of the printed photographs. The lines were added twice using both white and black.

When Academic Press (now an imprint of Elsevier) approached Kaufman to produce a revised edition, a user survey suggested it should include colour images, more coronal sections and an update of the text from 1994 to 2012. Without the original electronic version this was never going to be possible and with Kaufman’s failing health an agreement was put in place that the original histological slides would be re-digitised in colour and at high resolution by the Edinburgh Mouse Atlas Group, and made freely available both to the community and to Elsevier for a revised and online edition. The open-access online images would have the same annotations as in the original book but no written content. The revised edition would include all the original copyrighted material and would be available for purchase.

The eHistology resource

Here, we announce the web publication of the open access mouse embryo eHistology resource (www.emouseatlas.org/emap/eHistology/). This delivers the new, re-digitised high-resolution images of the histology sections that were photographed for the original atlas, as a series of annotated ‘zoom-viewer’ images on the web. The images are organized with the same plate and image numbering of the original atlas and in addition to online access are freely available for download from the University of Edinburgh’s DataShare resource with associated metadata. With each dataset the download includes:

(1) Full-resolution jpeg format images, up to 35,000×55,000 pixels at 0.34 μm per pixel, enabling histological sections to be viewed at cellular resolution.
(2) Details of the embryo, plate and image with respect to the original atlas.
(3) A full list of Kaufman annotations, with their respective (x,y) coordinate locations within the given image.
(4) EMAPA ontology IDs for each annotation and, where identified, a Wikipedia entry.
(5) The URL of the specific image in the eHistology resource for linking and citation.

The histological processing for the embryo sections is detailed in The Atlas of Mouse Development (Kaufman, 1994, p. 2). For the eHistology resource, we have re-digitised the sections using the Zeiss DotSlide slide scanner with a ×20 objective to produce images with a pixel resolution of 0.34 μm and in full colour. The images are converted using the VIPs image processing application (Martinez and Cupitt, 2005) to a pyramidal tiff format that are used by the Image Internet Protocol 3D server (IIP3D) (Husz et al., 2012) coupled with a JavaScript user interface developed in-house. The interface will run in most web browsers, although, because of the non-standard behaviour of web browsers, it functions best in Firefox (support.mozilla.org/en-US/products/firefox), which is freely available for all operating systems.

Fig. 2. Screen shot of the eHistology viewer. (A) The main view window shows the new image at a resolution approximately as published in the paper Atlas. The sub-regions highlighted and redisplayed illustrate the resolution available using the online zoom capability. (B) The plate detail is made visible by clicking the ‘i’ information icon. (C) The image context menu allows alternate view modes, measurement and image download. (D) The annotation links are displayed by = ‘clicking’ on an annotation flag in the image.

Fig. 2 shows the eHistology viewer corresponding to Plate 40a, image d (Kaufman, 1994, p. 344) in the original atlas. The index on the right-hand side shows the annotations defined by Kaufman in the original; ‘mouse-over’ or selecting the term will show the location in the image of that structure. Similarly, putting the screen

cursor over the image will cause the nearest annotations to be displayed. Selecting a term leaves the flag permanently visible and clicking on a term will provide access to other information and data, in particular the eMouseAtlas (Richardson et al., 2014) and GXD/MGI (Smith et al., 2014) resources (queried using the EMAPA ID of that tissue) and the licenced material available from Elsevier. In addition, it is possible to inspect the image at high resolution and to make size measurements of any given structure.

The resource provides a simple index (www.emouseatlas.org/emap/eHistology/index.php) based on the plate and image letter of the original atlas that can be reset from any given view. This will be extended to include a search option for any annotation term and anatomy (EMAPA) ID. Individual views of each section can be reached via a parameterised URL for the purposes of linking to a specific view. This will allow other resources and websites to provide links directly to the respective image, by-passing the index page.

This eHistology resource is a novel collaboration to provide an open-access resource linked to a definitive reference book that is still under copyright, thus providing benefit to the scientific community and extending the value to the publisher. With the images now public, it opens the door to community contribution in terms of more-detailed and extensive annotation, as well as linking out and integrating a whole range of anatomical and histological resources.

References

Husz, Z. L., Burton, N., Hill, W., Milyaev, N. and Baldock, R. A. (2012).Web tools for large-scale 3D biological images and atlases. BMC Bioinformatics 13, 122.

Kaufman, M. H. (1994). The Atlas of Mouse Development. Amsterdam, The Netherlands: Elsevier Academic Press.

Martinez, K. and Cupitt, J. (2005). VIPS – a highly tuned image processing software architecture. In Proceedings of IEEE International Conference on Image Processing 2, 574-577.

Richardson, L., Venkataraman, S., Stevenson, P., Yang, Y.,Moss, J., Graham, L., Burton, N., Hill, B., Rao, J., Baldock, R. A. et al. (2014). EMAGE mouse embryo spatial gene expression database: 2014 update. Nucleic AcidsRes. 42,D835-D844.

Smith, C. M., Finger, J. H., Hayamizu, T. F., McCright, I. J., Xu, J., Berghout, J., Campbell, J., Corbani, L. E., Forthofer, K. L., Frost, P. J. et al. (2014). The mouse Gene Expression Database (GXD): 2014 update. Nucleic Acids Res. 42, D818-D824.

(1 votes)

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It is our great pleasure to invite you to participate in the first joint meeting of the Portuguese, British and Spanish Societies for Developmental Biology, a unique occasion to gather the three scientific communities and celebrate science without frontiers.

The meeting features an outstanding line up of speakers, and there will also be 16 talks from participants, selected from submitted abstracts, so this is a great opportunity for junior researchers to present their exciting work to fellow developmental biologists.

The meeting is organized in a beautiful location (Alfamar Beach and Sport Resort, Algarve, http://www.alfamar.pt) and the schedule shall allow plenty of time to enjoy the social and sports activities that will be available. This will be a “family-friendly” meeting, and there will be family accomodation and daily activities for children. So, take the opportunity to bring your family and enjoy a great meeting, in a beautiful location and, hopefully, in a nice and warm climate.

Registrations are now open!! Check at www.spbd-meeting2015.com

Travel Grants are available for BSDB, SPBD or SEBD members (information at the above website)

For BSDB, please apply to http://bsdb.org/membership/meeting-grants/company-of-biologists/

Hurry up!

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Here are the highlights from the current issue of Development:

Hippo signalling: not just for growth

The Hippo signalling pathway regulates organ growth: activation of the pathway inhibits proliferation and promotes apoptosis. The core pathway consists of two kinases, Hippo and Warts, along with their adaptor proteins. Warts phosphorylates and thus inactivates the transcriptional co-activator Yorkie, whose target genes include regulators of cell proliferation and survival. Upstream of Warts, various factors impact on kinase activity, including cytoskeletal and polarity regulators. While Hippo signalling is best known for regulating growth, on p. 2002 Madhuri Kango-Singh, Amit Singh and colleagues define a function for Yorkie in regulating differentiation in the Drosophila eye. Manipulation of the Hippo pathway is well known to regulate eye size, but here the authors find that mis-expression of Yorkie inhibits neuronal differentiation. Mechanistically, they find that Yorkie promotes the expression of Wingless, a known inhibitor of morphogenetic furrow progression and hence differentiation. Intriguingly, the two functions of the pathway – in regulating growth and in controlling differentiation – appear to be separable: while growth is regulated by the Hippo kinase, differentiation is controlled by the upstream regulators Fat and Dachs, which bypass Hippo. These data add to an emerging picture of Hippo signalling as a regulator not only of growth, but also of other developmental processes.

An efficient protocol for hair cell differentiation

The hair cells (HCs) of the inner ear mediate both our auditory and our vestibular senses. Following loss or damage, mammalian HCs show very limited capacity to regenerate, creating a therapeutic need to generate new HCs in vitro for cell replacement strategies. Domingos Henrique and co-workers now report a relatively simple and efficient protocol for deriving HCs from mouse embryonic stem cells, by expression of key transcription factors involved in HC differentiation during development (p. 1948). Co-expression of Atoh1 (traditionally considered the ‘master regulator’ of HC differentiation) with Gfi1 and Pou4f3 can efficiently induce a HC gene expression signature in embryoid body cells. Efficiency is further increased by either Notch pathway blockade or retinoic acid treatment. The resulting cells, termed induced HCs (iHCs) also show morphological and functional signs of HC differentiation: incipient stereociliary bundles and the presence of functional mechanotransduction channels. However, the iHCs are not fully mature, implying that additional extrinsic or intrinsic factors are required to direct terminal differentiation. Although this is not the first report of in vitro differentiation of HCs, the greater simplicity and efficiency of this protocol marks a significant step towards the goal of generating HCs in culture for research and therapeutic purposes.

3D auxin flows in phyllotaxis

The arrangement of leaves and flowers around the stem typically follows a stereotyped phyllotactic pattern, with the location of a new leaf defined by the positions of previously specified ones. This is controlled by the plant hormone auxin. In the meristem epidermis, auxin accumulates at the site of future primordia, generating intervening regions of auxin minima where no new organ can form. Auxin-dependent phyllotactic patterns can be computationally modelled in two dimensions, considering only the epidermal layer. However, auxin flows into lower layers of the primordium, where the incipient midvein is thought to drain auxin away from the meristem. The contribution of this auxin drainage to leaf development has been hard to assess, but Didier Reinhardt and co-workers (p. 1992) have employed sophisticated live imaging and cell ablation techniques to study the role of the midvein in organ formation and positioning. The authors specifically ablate the future midvein, while leaving overlying layers intact. This leads to a transient auxin accumulation and consequent widening of the primordium. Although the damage is rapidly healed and subsequent leaf development is normal, phyllotaxis is disrupted, spacing of adjacent primordia is aberrant – revealing the importance of the incipient midvein in phyllotaxis.

More than one way to make an appendage

The eggs of drosophilid species are characterised by the presence of dorsal appendages, which arise from the follicular epithelium. Different species display different numbers and morphologies of appendages, but little is known about how these differences arise from a morphological perspective. Now, on p. 1971, Miriam Osterfield and colleagues compare the morphogenesis of the D. melanogaster paired appendages with appendage formation in two other species, S. pattersoni and D. funebris. In D. melanogaster, appendage morphogenesis is at least partly driven by cell-cell rearrangements between the cells that will form the floor of the appendage and neighbouring operculum cells. However, the authors find that this morphogenetic mechanism is not conserved in S. pattersoni, where eggs have variable numbers of appendages – typically five to eight. Instead, tube morphogenesis is driven by floor cell elongation: those floor cells that will form the appendage elongate dramatically without a similar exchange of neighbours. In D. funebris, both cell elongation and cell rearrangements contribute to appendage formation. That the mechanisms underlying appendage formation differ so dramatically suggests a surprising diversity in cellular behaviours during morphogenesis between even closely related species.

PLUS:

How to make a dopaminergic neuron

Ernest Arenas, Mark Denham and Carlos Villaescusa summarise recent efforts to generate human midbrain dopaminergic neurons in vitro, from pluripotent stem cells or from somatic cells via direct reprogramming. See this Primer on p. 1918

The origin of the mammalian kidney

Minoru Takasato and Melissa Little discuss recent advances in the directed differentiation of pluripotent cells into kidney tissues, and how these inform our understanding of human renal development.  See the Meeting Review on p. 1937

At new heights- endodermal lineages in development and disease

Elke Ober and Anne Grapin-Botton review the recent Keystone conference on Endoderm Lineages in Development and Disease, which took place last February in Colorado, USA, highlighting recent major advances in the field. See the Meeting Review on p. 1912

The atlas of mouse development eHistology resource

Over two decades after the publication of ‘The Atlas of Mouse Development’ by Professor Mathew Kaufman, Baldock and colleagues announce a new online resource that provides free access to the histological images and their annotations. See the Spotlight on p. 1909

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Georgas et al. have presented a comprehensive update to the anatomical ontology of the murine urogenital system. These updates pertain to the lower urinary tract, genital tubercle and associated reproductive structures, covering stage E10.5 through to adult. The updates have been based on recently published insights into the cellular and gross anatomy of these structures, tissue layers and cell types. Included are representative schematic illustrations, detailed text descriptions and molecular markers that selectively label muscles, nerve/ganglia and epithelia of the lower urogenital system. The revised ontology will be an important tool for researchers studying urogenital development/malformation in mouse models and will improve our capacity to appropriately interpret these with respect to the human situation.

The updated ontology and definitions (including features, synonyms, molecular markers and lineage relationships where established) are available on the GUDMAP website (http://www.gudmap.org/Resources/Ontology/index.php). The ontology has been entered into the EMAP mouse embryo ontology (Hayamizu et al., 2013) and published on the Open Biological and Biomedical Ontologies web resource (http://www.obofoundry.org/).

(1 votes)

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On the twentieth anniversary of the Nobel Prize for research in fly embryonic development

By Peng Kate Gao

2015 marks the twentieth year since developmental biologists Edward B. Lewis, Christiane Nüsslein-Volhard and Eric F. Wieschaus won the Nobel Prize for their discoveries on the genetic control of early embryonic development (Figure 1). This anniversary is a good time for us to revisit their groundbreaking discoveries and consider the impact on developmental biology. Using the fruit fly Drosophila melanogaster as their experimental system, the three scientists discovered profound principles governing the formation of body segments, and the formation of organs in individual segments. In subsequent years, the very same mechanisms, involving similar genes and molecules, have been shown to operate in early development throughout the animal kingdom, and thus their pioneering work in the fruit fly might one day help us understand human development.

Edward B. Lewis’s research and the four-winged fly

Lewis pioneered fine-structure genetic mapping in Drosophila. Using X-ray radiation or ethyl methanesulfonate (EMS, an alkylating agent that causes genetic mutations in the fruit fly), he recovered various mutants that displayed homeotic transformations—one organ transformed into another. From the late 1940s to the early 1950s, Lewis focused increasingly on a cluster of genes, which he named the bithorax complex (BX-C). Mutations in this gene cluster led to segmental transformations. The embodiment of this research is the famous four-winged fly, in which the third thoracic segment is transformed into the second thoracic segment, resulting in flies where the halteres (the balance organs of a fly) are converted into an extra pair of wings (Figure 2). By mapping the mutations that gave rise to this striking phenotype to BX-C, Lewis demonstrated that simple genetic mutations could cause dramatic changes in the body plan. This concept motivated a generation of geneticists, including Nüsslein-Volhard and Wieschaus, to search for additional genes underlying embryonic development and patterning.

Lewis also discovered the colinearity principle for the Hox cluster of homeotic genes. He found that genes in this cluster are linearly arranged on the chromosome, and their physical order parallels the time of expression during development and corresponds to the body segments they control (Figure 3). An even greater surprise came later, when Hox genes were found to be among the most evolutionarily conserved gene families, and the principle of colinearity holds true for almost all living animals, including vertebrates. These findings revolutionized our understanding of how animals and their organs have evolved, and rooted the emergence of a new discipline in molecular genetics: evolutionary developmental biology, or evo-devo.

Christiane Nüsslein-Volhard, Eric F. Wieschaus and their pioneering screens for segmentation mutants

Inspired by the early studies of Lewis, Nüsslein-Volhard and Wieschaus carried out a series of large-scale genetic screens between 1978 and 1981 at the European Molecular Biology Laboratory (EMBL) in Heidelberg, searching for genes that altered the segmentation pattern of Drosophila embryos–as assayed by the morphology of the cuticle. After analyzing some 40,000 flies, they found fifteen such genes. These genes can be categorized into three classes based on their effects on segmentation (Figure 4):

1, “gap genes,” which subdivide the embryo into multiple regions along the anterior-posterior axis. Mutations in gap genes lead to fewer segments and create gaps in the anterior-posterior pattern of the developing organism.

2, “pair rule genes,” which establish pairs of segments. Mutations in pair rule genes affect every other body segment. For example, loss of even-skipped causes embryos to have only odd numbered segments.

3, “segment polarity genes,” which establish the anterior-posterior axis of each segment.

Nüsslein-Volhard and Wieschaus’ work provided new insights into the genetic mechanism underlying the step-wise development of Drosophila embryos. More importantly, it showed that genes controlling particular aspects of development could be systematically identified by virtue of their mutant phenotype. This groundbreaking work laid the foundation for many other genetic screens to identify genes that control the body plan of flies, and for analyses of how these genes operate together to orchestrate the developmental program of Drosophila as well as vertebrates—which has been a central focus of developmental biology ever since.

The legacy

Almost four decades have passed since Lewis, Nüsslein-Volhard and Wieschaus published their landmark studies in Drosophila, yet the influence of their findings on developmental biology is profound and long lasting. Through their elegant experiments, they demonstrated that the intricate and seemingly hopelessly complex process of development could be dissected using a good model system together with a carefully designed experimental strategy. Insights gained from studying the fruit fly have paved the way to understanding similar developmental processes in other organisms, including vertebrates, which, albeit separated from the fruit fly across vast evolutionary distances, obey similar rules and are controlled by similar gene networks. This has deep implications for basic science as well as medicine, as mentioned in the Nobel press release in 1995, the breakthrough achieved by the three scientists will one day “help explain congenital malformations in man.”

Additional information:

An interview with Nüsslein-Volhard and Wieschaus about their research.

A talk by Wieschaus explaining the design and execution of their experiments.

References: 

The Nobel Prize in Physiology or Medicine 1995 – Press Release. Nobelprize.org.

Lewis, E.B. (1978) A gene complex controlling segmentation in Drosophila. Nature 276, 565-570

Nüsslein-Volhard, C. and Wieschaus, E. (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287, 795-801

Crow, J.F. and Bender, W. (2004) Edward B. Lewis, 1918-2004. Genetics 4, 1773-1783.

Nüsslein-Volhard, C. (1996) Gradients that organize embryo development. Scientific American, August 1996.

(5 votes)

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Welcome to the Eublephosphere!
Eublephosphere (noun) – A place in which those who study the leopard gecko (Eublepharis macularius) reside.

Our names are Noeline Subramaniam and Kathy Jacyniak and we are Master’s students at the University of Guelph in Ontario, Canada. Under the supervision of Dr. Matthew Vickaryous, we have become budding regenerative biologists! Our research laboratory investigates the most fundamental question in biology: why are some tissues and organisms able to regenerate, whereas others cannot? Our model for these investigations is the leopard gecko (Eublepharis macularius), a popular reptile in the pet trade.

Research Focus

Figure 1: Members of the Vickaryous lab from left to right: Dr. Matt Vickaryous, Kathy Jacyniak, Noeline Subramaniam and Emily Gilbert

Ongoing research in our lab aims to identify and understand the biological mechanisms that permit and promote scar-free wound healing and regeneration.Emily, a PhD candidate, is examining the role of neural stem/progenitor cells in the spinal cord and the brain in response to regeneration, Noeline is investigating the role of angiogenesis in scar formation, and Kathy is exploring the role of cardiac stem/progenitor cells in the heart. If you would like to learn more about the research conducted by the Vickaryous lab, check out our website: http://www.vickaryouslab.com/. You can also follow us on Twitter @VickaryousLab, including our infamous #FluorescentFridays.

Figure 2: Dorsal view of a gecko with a beautiful original tail. This gecko was an environmental control for one of our previous studies.

Why lizards?

Many species of lizards are able to self-detach a portion of their tail to avoid predation, and then regenerate a replacement. Tail detachment, or caudal autotomy (‘self-cutting’), is a dramatic – and somewhat deceptive – phenomenon. For most species (including leopard geckos), the tail is autotomized within a vertebra at a location known as a fracture plane (essentially a non-mineralized gap in the vertebral centrum). In addition, the main arterial supply to the tail (the caudal artery) develops a regular series of muscular sphincters, with one sphincter located in advance of each fracture plane. Therefore, the site of tail loss rarely bleeds more than a couple of drops. Tail regeneration then begins spontaneously following caudal autotomy.

Why leopard geckos?

Figure 3: The leopard gecko (Eublepharis macularius) is the model we use in our lab. They can spontaneously regenerate their tail following tail loss.

Although many lizards can regenerate their tails, the husbandry requirements for some species can be challenging (e.g., the lizards are aggressive or shy, have narrow ranges of preferred temperature and humidity, particular and unusual dietary and habitat preferences, and/or are intolerant of handling). As a result, early work on lizard tail regeneration tended to focus on a few types of locally available (and wild caught) species kept over short periods of time. However, with the increasing popularity of reptiles a pets, some lizards – including leopard geckos – are now captive bred and (at least in North America) widely available. Leopard geckos are hardy, accept being handled, and have relatively simple husbandry requirements: a plastic enclosure similar in size to those used for rats and mice; a water dish; a couple of hide boxes; a heat pad under one end (to establish a thermal gradient – leopard geckos are ectotherms); and escape-proof lid (see below).

Leopard gecko fun facts:

– Caudal autotomy is not necessary for regeneration. Tails surgically amputated outside the fracture plane still regenerates
– They are members of the Eublepharidae – the ‘true eyelid’ geckos. Unlike other geckos, they have movable eyelids
– They are native to parts of Pakistan, Afghanistan, India and possibly Iran
– They have temperature-dependant sex determination – the temperature of the environment during the embryonic period helps determine the sex of the offspring

A typical day in the Vickaryous lab:

We typically start the day with a cup of coffee/tea and a discussion about our experimental plans for the day. We manage our own leopard gecko colony, and everyone has to pitch in with the daily feedings and weekly weigh and measure adventures. After the geckos have been attended to there is a good chance someone in the lab will be serially sectioning and staining tissue. Not only do we love our histology, but learning to section seems to be a rite of passage in our lab…

Figure 4: Undergraduate students Rebecca McDonald (left) and Alaina Macdonald (right) working in our histology prep lab. The majority of our time spent here includes processing, embedding, sectioning and staining tissues we use to study regeneration

Feeding, housing and maintaining leopard geckos:

Our gecko colony is maintained in an environmental chamber (about 28˚C) here at the University of Guelph. Leopard geckos are not terribly social, so we house each one separately – this also makes keeping track of who’s who much easier. Our gecko enclosures are roughly 36cm x 22cm x 22cm in size, and topped by a perforated lid. Although leopard geckos lack subdigital adhesive pads, they have small claws and are capable climbers (and aspiring escape artists). Fortunately, they seem to prefer showing off their talents rather than following through with the getaway.

Leopard geckos eat live prey, and we feed ours mealworms (larval Tenebrio molitor, the mealworm beetle) dusted with a calcium and vitamin D3 (cholecalciferol) powder. The use of calcium and vitamin D3 is necessary in that it helps prevent metabolic bone disease, a nasty group of disorders that can lead to brittle or distorted limb elements and jaws, paralysis and reduced growth.

Weekly duties include cleaning and changes cages, and weighing and measuring geckos. Both require a certain degree of gecko wrangling skills, and tolerance of gecko urine. Although leopard geckos are typically docile and easy to handle, they will occasionally let loose a stream – especially if you forget to wear a lab coat.

Figure 5: Aerial view of a standard gecko enclosure. Features include: two small huts and a bowl of water.

Impact of ongoing research:

Tail replacement by leopard geckos is a striking example of a naturally evolved mechanism of multi-tissue regeneration. As one of the closest living relatives to mammals, leopard geckos provide a powerful platform to study the biology of regeneration, with numerous biomedical implications. Unlike other species, leopard geckos (and other lizards) can voluntarily self-detach the tail and have a variety of structural adaptations to minimize (or at least localize) tissue damage. Thus, autotomy-mediated tail loss is arguably a less-invasive alternative to amputation to initiate the regeneration program.

Follow us on Twitter: @VickaryousLab

Website: http://www.vickaryouslab.com/

Figure 6: Tail regeneration (in dorsal view). Left to right: the original tail, two regenerating tails and variation in two complete regenerate tails.

This post is part of a series on a day in the life of developmental biology labs working on different model organisms. You can read the introduction to the series here and read other posts in this series here.

(10 votes)

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This cartoon was first published in the Journal of Cell Science. Read other articles and cartoons of Mole & Friends here.

To read part I- ‘The imposter’ click here. To read part II- ‘The teaching monster’ click here.

(1 votes)

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Pint of Science is a science outreach organization that holds an annual festival across 9 countries (UK, Ireland, France, Italy, USA, Australia, Spain, Germany and Brazil) in 6 major themes, to bring the deeper, ground-breaking questions of science and the researchers working on them in contact with public at the local watering holes. The 2015 festival was from May 18^th to 20^th. I was fortunate enough to be invited to talk in the Pint of Science USA – Boston/Cambridge on the theme of Brain Games: From Development to Empathy gaps. It was a fantastic and engaging evening. I had the distinct pleasure of sharing the microphone with a brilliant fellow researcher Dr. Emile Bruneau from MIT who works on using neuroscience tools to discover new ways of understanding and solving conflict resolution issues across different tense areas in the world. I was given the opportunity to go first and talked about “Coding in Biological Systems: Bioelectrical Control of Tissue Identity and Anatomy” for about 10-15 mins. The transcript of my talk can be found below in this post. This was followed by a barrage of very interesting and engaging questions from the audience. Then it was Dr. Bruneau’s turn to speak and I had the distinct pleasure of being his guinea pig for an onsite experiment/demonstrations. I thoroughly enjoyed it and I believe everyone had a blast.  Many deep questions and discussions followed his talk. I had the good fortune of discussing science questions, thoughts and ideas with Dr. Bruneau and some of the audience members after the event. A wonderful effort and event organization by the Pint of Science USA – Boston/Cambridge coordinators Eleana Manousiouthakis, Daniel Whittet, and Shannon Spreen and the Pint of Science community all together in making this happen. The events’ major sponsors were elife, AHA consulting engineers, USGBC Massachusetts, BGlo and D!A.

Dr.Emile and myself have a nice discussion after our talks

Title: Coding in Biological Systems: Bioelectrical Control of Tissue Identity and Anatomy

“How many of you know who a potter is? Ok for those who may not know, potter is a person who creates these beautiful pots and structures out of clay/mud. And the way that this person does this is; they have a spinning wheel on which they place a limp of moist clay and give it beautiful shape by applying forces with their hands.

Now in nature you see all kinds of beautiful shapes and structures, from that of butterflies to various birds all the way to humans. How are these shapes in nature formed? There is no external force shaping them as they develop. So where is the information for shape structure and organs stored? All animals develop from an embryo. An embryo is a single cell with one piece of genetic information. So is the information for shape and structure stored in the genetics? To find out lets do a thought experiment. Say an alien comes down to earth and hands us humans a piece of genetic information of an animal that we have never seen before. Will we be able to predict this animal’s shape, structure, organs and functions of those organs based only on the genetics of it? The answer is no! This does not mean genetics is not important. Genetics does carry important information but not all the information, only a fraction of this information. Where else then could the information for shape and structure be present? Every cell, including the developing embryo sits in a multidimensional environment where it is sensing or gathering information from all these dimensions. One of these dimensions is genetics, others including mechanical forces, chemical signals and biophysical or Bioelectric signals. We work on understanding what information is stored in bioelectrical signals and how powerful this information is.

What are bioelectrical signals? They are not externally applied electrical currents, but are endogenous (from within) currents. They are also not very fast and transient currents like one sees in the neurons. They are rather very slow currents changing over very long periods of time like hours to days! Now take any cell. It has a membrane that separates its inside from its outside. In this membrane there are proteins that act as pumps and channels. These proteins use a lot of energy to shuttle charged molecules like sodium, potassium, chloride etc, in such a way that the inside of the cell is negative and the outside positive; thus converting every cell into a battery. This voltage difference across the membrane is called membrane voltage (Vmem) and for each cell it is about 10s of mV. Now if you take a sheet of cells and look at the Vmem of cells you don’t see uniform Vmem but rather beautiful patterns of Vmem. This is highly evident in developing embryos where one sees these beautiful patterns of Vmem that occur as the embryo develops. So what information do these bioelectrical patterns contain?

To study this we use frog embryos which are experimentally practical for various reasons. We have identified one of the patterns that is critically involved in eye development. What is remarkable is that if we imprint that eye pattern elsewhere of the embryo say for example on the gut, we end up forming a whole eye on the gut of the frog tadpole. Similarly we are able to form eyes on the tail and even butt of the tadpole! What is even more remarkable is that the tadpoles are able to see through these extra eyes and their brains are able to process the visual information coming from them no matter where they physically might be present! This is done using a robot which not only records the behavior of these animals but is able to teach them and test them how much they have learned. We have now done similar experiments for bioelectric control of brain tissues as well, and are able to induce brain tissues even in the tail of the tadpole.

So what is the purpose of all this? This will help us know where and how the information for shape and structure is stored within bioelectrical signals and how it is read and implemented. This is very important for purposes of regenerative medicine, where if there is any traumatic injury we can use this to regenerate the tissues or organs. Another use is once we know this information encoding we can detect birth defects very early on before they manifest and may even be able to add that information back and correct the defect. Lastly cancers can be viewed as lump of cells that have lost the information of structure, shape and function. If we can implant the right information into the tumors we might be able to have them differentiate and incorporate into normal tissues and perform normal functions. Ok at this point I will stop and take any questions you all may have for me.  “

(1 votes)

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