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Tabin, C. J.

Publications and source records attributed to Tabin, C. J..

11 recordsLinked to original sources

Late embryonic expansion of a novel bone ridge underlies the evolutionary transformation of cylindrically shaped forelimb bones into the flattened skeleton of the penguin flipper

The evolution of flippers for wing-powered diving in penguins is a striking example of tetrapod limb specialization. The modern penguin flipper is structurally reinforced by a characteristic dorsoventral flattening of the long bones accompanied by a reduction in distal forelimb musculature, features which emerged convergently in flightless diving birds and aquatic mammals. While an extensive fossil record informs the morphological sequence through which these changes occurred, the evolutionary pressures and developmental mechanisms underlying these modifications are unknown. We find that in avian and mammalian forelimbs, a flattened bone morphology only emerged in aquatic lineages that lost ancestral modes of locomotion, including in flightless diving birds, pinnipeds, and cetaceans. Using penguin embryos as an accessible model for investigating flipper development, we demonstrate that early patterning of forelimb musculoskeletal morphology is similar to that seen in forelimbs of non-aquatic birds. Instead, later modifications of gene expression and cell and tissue behaviors underlie flipper phenotypes. Thus, we find that in the early penguin forelimb, the initial cues that pattern the muscle do not differ from other avian species, however late embryonic changes in proliferation result in dramatic reduction of muscle. Likewise, forelimb bones in penguins initially have similar cross-sectional proportions to those in flighted birds. The shape of these bones is, however, remodeled late in embryonic development through a process that shares molecular hallmarks with bone ridge formation at tendon attachment sites. In these bones, ridge-forming tissue initiates at the ends of the bones (the epiphyses) and extends into tendon-like connective tissue along the lateral edges of the bone, widening the long bones along the anterior-posterior axis and producing a flattened bone. Using spatial transcriptomics and comparative genomic tools we determine that differentially expressed genes between the ridge-forming tissues and long bone cartilage are significantly enriched for signals of selection in the penguin lineage and that these genes may also be convergently evolving in marine mammals. Together, these data show that the evolution of musculoskeletal morphology in the penguin flipper occurred through expansion or novel deployment of molecular programs typically associated with tendon-attachment sites during late embryonic development.

developmental biology↗

Pitx2 modulates Fgf10 dosage to initiate asymmetric lung morphogenesis

Most of the visceral organs are anatomically asymmetric across the left-right axis. These asymmetries can be traced to a well-studied molecular cascade leading to left-sided gene expression, including Pitx2, in the mesoderm. Yet how these early differences in gene expression are converted into differential shaping of organs at later stages remains incompletely understood, and for many organs, such as the lung, the question has not even been explored. Meanwhile, the signaling pathways responsible for the morphogenesis of the lung have been intensively studied, but no insight has been reported regarding whether they should differ on the left and right sides. Here we identify Fgf10 as a Pitx2-sensitive signal in the mesenchyme of the developing mouse lung. Fgf10 expression increases as Pitx2 decreases, making the right lung, which lacks Pitx2 expression, grow faster than the left during the budding stage. Modulating Fgf10 dosage in the left mesenchyme is sufficient to alter lung budding asymmetry. At the cellular level, the faster growth of the right lung is established by increased levels of epithelial proliferation, without significant differences in directional migration into the mesenchyme. Conditional genetics further show that Pitx2 acts during the budding stage to establish later branching asymmetry. Thus, Pitx2 converts left-right mesenchymal identity into organ asymmetry by quantitatively tuning Fgf10-dependent epithelial growth during early organogenesis.

developmental biology↗

Convergent flow-mediated mesenchymal force drives embryonic foregut constriction and splitting

The transformation of a two-dimensional epithelial sheet into various three-dimensional structures is a critical process in generating the diversity of animal forms. Previous studies of epithelial folding have revealed diverse mechanisms driven by epithelium-intrinsic or -extrinsic forces. Yet little is known about the biomechanical basis of epithelial splitting, which involves extreme folding and eventually a topological transition breaking the epithelial tube. Here, we leverage tracheal-esophageal separation (TES), a critical and highly conserved morphogenetic event during tetrapod embryogenesis, as a model system for interrogating epithelial tube splitting both in vivo and ex vivo. Comparing TES in chick and mouse embryos, we identified an evolutionarily conserved, compressive force exerted by the mesenchyme surrounding the epithelium, as being necessary to drive epithelial constriction and splitting. The compressive force is mediated by localized convergent flow of mesenchymal cells towards the epithelium. We further found that Sonic hedgehog (SHH) secreted by the epithelium functions as an attractive cue for mesenchymal cells. Removal of the mesenchyme, inhibition of cell migration, or loss of SHH signaling all abrogate TES, which can be rescued by externally applied pressure. These results unveil the biomechanical basis of epithelial splitting and suggest plausible mesenchymal origins of tracheal-esophageal birth defects.

developmental biology↗

Integration of sexual dimorphism and left-right asymmetry in the development of the duck syrinx

Embryonic morphogenesis is regulated across multiple dimensions. In ducks, the syrinx, the avian vocal organ, undergoes morphogenic processes that result in both left-right asymmetric and sexually dimorphic development. Although these properties are thought to be controlled by the NODAL-PITX2 left-right signaling cascade and the sex steroid pathways, how these mechanisms work together to produce an asymmetric structure in a sexually dimorphic manner remains unclear. Here, we first establish evidence for sexual selection driving the evolution of the duck syrinx. During its development, we observe that PITX2 is expressed on the left side in both male and female ducks, although not in other birds. Asymmetric activation of PITX2 in this domain is triggered by bilateral BMP signaling but is limited to the left side by left-specific stably accessible chromatin established during an earlier asymmetric wave of PITX2 expression. Ultimately, there is an induction of left-specific WNT and BMP signaling in the syrinx primordium, which synergistically elevates cell proliferation on the left, leading to asymmetric growth. Estrogen receptor expression is also shown to be induced on the left side of the forming syrinx. This has no effect in males, but in females where the hormone is present, estrogen signaling reduces left-sided cell proliferation, thus promoting bilaterally symmetric growth. These data demonstrate how sexually dimorphic left-right asymmetry can be integrated to produce an adaptive trait.

developmental biology↗

Shifts in embryonic oxygen levels cue heterochrony in limb initiation

Heterochrony, or the alteration of developmental timing, is an important mechanism of evolutionary change. Avian species display synchronized growth of the forelimbs and hindlimbs, while mammalian species show delayed hindlimb development. We find that mammalian limb heterochrony is evident from the start of limb bud formation, and is associated with heterochronic expression of T-box transcription factors. This heterochronic shift is not due to changes in cis-regulatory sequences controlling T-box gene expression, but unexpectedly, is dependent upon differential oxygen levels to which avian and mammalian embryos are exposed prior to limb initiation. This is mediated, at least partially, by an NFKB transcription factor, cRel, and by the oxygen-sensing transcription factor hypoxia inducible factor alpha (Hif1a). Together, these results provide mechanistic understanding of an important example of developmental heterochrony and exemplify how the maternal environment regulates timing during embryonic development.

developmental biology↗

A dynamic Hedgehog gradient orients tracheal cartilage rings

The patterning of periodic stripes during embryonic development generates similar structures that repeat at regular spatial intervals within a tissue. These patterns are often attributed to a Turing-like mechanism, which self-organizes characteristically spaced stripes, but these patterns are predicted to be disorganized. Conversely, well-oriented, parallel stripes are often observed in nature. We investigate this phenomenon during the formation of the cartilage rings that support the amniote airway. We find evidence that a Turing-like mechanism underpins the formation of the repeating cartilage elements. Additionally, SHH is transiently expressed in a thin dorsal domain along the length of the developing trachea, resulting in a dorsoventral gradient of Hedgehog activity that recedes over time. Using mathematical modelling, we predict that the spatiotemporal dynamics of the gradient are required to organize the stripes into parallel rings. Comparing in silico predictions with experimental SHH manipulations shows that the Hedgehog gradient is essential for proper tracheal cartilage patterning.

developmental biology↗

Hox genes modulate physical forces to differentially shape small and large intestinal epithelia

The small and large intestines arise from a common primordial gut tube but ultimately become specialized in both form and function. While the midgut forms villi, the hindgut develops flat, brain-like sulci that resolve into heterogeneous outgrowths. Gut compartment identities are demarcated early in development via Hox genes, which are highly conserved, master regulators of spatial patterning in the embryo. Yet, how these factors trigger regional morphogenesis has remained a mystery. Combining mechanical measurements and mathematical modeling, we demonstrate that the posterior Hox gene Hoxd13 regulates biophysical phenomena that shape the hindgut lumen. We further show that Hoxd13 acts through the TGF{beta} pathway to thicken, stiffen, and promote isotropic growth of the subepithelial mesenchyme; together, these features generate hindgut surface patterns. TGF{beta}, in turn, promotes collagen deposition to affect mesenchymal geometry and growth. We thus identify a cascade of events downstream of genetic identity that direct posterior intestinal morphogenesis.

developmental biology↗

In ovo electroporation of chick limb bud ectoderm

Deciphering how ectodermal tissues form, and how they maintain their integrity, is crucial for understanding epidermal development and pathogenesis. However, lack of simple and rapid gene manipulation techniques limits genetic studies to elucidate mechanisms underlying these events. Here we describe have an easy method for electroporation of chick embryo limb bud ectoderm, enabling gene manipulation during ectoderm development and wound healing. Taking advantage of a small parafilm well that constrains DNA plasmids locally and the fact that the limb ectoderm arises from a defined site, we target the limb ectoderm forming region by in ovo electroporation. This approach results in efficient transgenesis of the limb ectodermal cells. Further, using a previously described Msx2 promoter, gene manipulation can be specifically targeted to the apical ectodermal ridge (AER), a signaling center regulating limb development. Using the electroporation technique to deliver a fluorescent marker into the embryonic limb ectoderm, we show its utility in performing time-lapse imaging during wound healing. This analysis revealed previously unrecognized dynamic remodeling of the actin cytoskeleton and lamellipodia formation at the edges of the wound. We find that the lamellipodia formation requires activity of Rac1 GTPase, suggesting its necessity for wound closure. Our method is simple and cheap, and permits high throughput tests for gene function during limb ectodermal development and wound healing.

developmental biology↗

A chromosome level genome of Astyanax mexicanus surface fish for comparing population-specific genetic differences contributing to trait evolution.

Identifying the genetic factors that underlie complex traits is central to understanding the mechanistic underpinnings of evolution. In nature, adaptation to severe environmental change, such as encountered following colonization of caves, has dramatically altered genomes of species over varied time spans. Genomic sequencing approaches have identified mutations associated with troglomorphic trait evolution, but the functional impacts of these mutations remain poorly understood. The Mexican Tetra, Astyanax mexicanus, is abundant in the surface waters of northeastern Mexico, and also inhabits at least 30 different caves in the region. Cave-dwelling A. mexicanus morphs are well adapted to subterranean life and many populations appear to have evolved troglomorphic traits independently, while the surface-dwelling populations can be used as a proxy for the ancestral form. Here we present a high-resolution, chromosome-level surface fish genome, enabling the first genome-wide comparison between surface fish and cavefish populations. Using this resource, we performed quantitative trait locus (QTL) mapping analyses for pigmentation and eye size and found new candidate genes for eye loss such as dusp26. We used CRISPR gene editing in A. mexicanus to confirm the essential role of a gene within an eye size QTL, rx3, in eye formation. We also generated the first genome-wide evaluation of deletion variability that includes an analysis of the impact on protein-coding genes across cavefish populations to gain insight into this potential source of cave adaptation. The new surface fish genome reference now provides a more complete resource for comparative, functional, developmental and genetic studies of drastic trait differences within a species.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genomics↗

Comparative evidence for the independent evolution of hair and sweat gland traits in primates

Humans differ in many respects from other primates, but perhaps no derived human feature is more striking than our naked skin. Long purported to be adaptive, humans unique external appearance is characterized by changes in both the patterning of hair follicles and eccrine sweat glands, producing decreased hair cover and increased sweat gland density. Despite the conspicuousness of these features and their potential evolutionary importance, there is a lack of clarity regarding how they evolved within the primate lineage. We thus collected and quantified the density of hair follicles and eccrine sweat glands from five regions of the skin in three species of primates: macaque, chimpanzee and human. Although human hair cover is greatly attenuated relative to that of our close relatives, we find that humans have a chimpanzee-like hair density that is significantly lower than that of macaques. In contrast, eccrine gland density is on average 10-fold higher in humans compared to chimpanzees and macaques, whose density is strikingly similar. Our findings suggest that a decrease in hair density in the ancestors of humans and apes was followed by an increase in eccrine gland density and a reduction in fur cover in humans. This work answers longstanding questions about the traits that make human skin unique and substantiates a model in which the evolution of expanded eccrine gland density was exclusive to the human lineage.

evolutionary biology↗

Insulin resistance in cavefish as an adaptation to a nutrient-limited environment

Periodic food shortage is one of the biggest challenges organisms face in natural habitats. How animals cope with nutrient limited conditions is an active area of study, of particular relevance in the context of the current increasing destabilization of global climate. Caves represent an extreme setting where animals have adapted to nutrient-limited conditions, as most cave environments lack a primary energy source. Here we show that cave-adapted populations of the Mexican Tetra, Astyanax mexicanus, have dysregulated blood glucose homeostasis and are insulin resistant compared to the river-adapted population. We found that multiple cave populations carry a mutation in the insulin receptor that leads to decreased insulin binding in vitro. Surface/cave hybrid fish carrying the allele weigh more than non-carriers, and zebrafish genetically engineered to carry the mutation similarly have increased body weight and insulin resistance. Higher bodyweight may be advantageous in the cave as a strategy to cope with infrequent food. In humans, the identical mutation in the insulin receptor leads to a severe form of insulin resistance and dramatically reduced life-span. However, cavefish have a similar lifespan to surface fish (of greater than fourteen years) and do not accumulate advanced glycated end products (AGEs) in the blood that are typically associated with progression of diabetes-associated pathologies. Our findings raise the intriguing hypothesis that cavefish have acquired compensatory mechanisms that allow them to circumvent the typical negative effects associated with failure to regulate blood glucose.

evolutionary biology↗