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Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ∼ 4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (r(e) = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (r(e) = 0.20-0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n ∼ 9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01 × 10(-37)), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31 × 10(-14)). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4 × 10(-10)). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.

The longitudinal growth of long bone, regulated by an epiphyseal cartilaginous component known as the “growth plate”, is generated by epiphyseal chondrocytes. The growth plate provides a continuous supply of chondrocytes for endochondral ossification, a sequential bone replacement of cartilaginous tissue, and any failure in this process causes a wide range of skeletal disorders. Therefore, the cellular and molecular characteristics of the growth plate are of interest to many researchers. Hedgehog (Hh), well known as a mitogen and morphogen during development, is one of the best known regulatory signals in the developmental regulation of the growth plate. Numerous animal studies have revealed that signaling through the Hh pathway plays multiple roles in regulating the proliferation, differentiation, and maintenance of growth plate chondrocytes throughout the skeletal growth period. Furthermore, over the past few years, a growing body of evidence has emerged demonstrating that a limited number of growth plate chondrocytes transdifferentiate directly into the full osteogenic and multiple mesenchymal lineages during postnatal bone development and reside in the bone marrow until late adulthood. Current studies with the genetic fate mapping approach have shown that the commitment of growth plate chondrocytes into the skeletal lineage occurs under the influence of epiphyseal chondrocyte-derived Hh signals during endochondral bone formation. Here, we discuss the valuable observations on the role of the Hh signaling pathway in the growth plate based on mouse genetic studies, with some emphasis on recent advances.

How do the various anatomical parts (modules) of the animal body evolve into very different integrated forms (integration) yet still function properly without decreasing the individual's survival? This long-standing question remains unanswered for multiple reasons, including lack of consensus about conceptual definitions and approaches, as well as a reasonable bias toward the study of hard tissues over soft tissues. A major difficulty concerns the non-trivial technical hurdles of addressing this problem, specifically the lack of quantitative tools to quantify and compare variation across multiple disparate anatomical parts and tissue types. In this paper we apply for the first time a powerful new quantitative tool, Anatomical Network Analysis (AnNA), to examine and compare in detail the musculoskeletal modularity and integration of normal and abnormal human upper and lower limbs. In contrast to other morphological methods, the strength of AnNA is that it allows efficient and direct empirical comparisons among body parts with even vastly different architectures (e.g. upper and lower limbs) and diverse or complex tissue composition (e.g. bones, cartilages and muscles), by quantifying the spatial organization of these parts-their topological patterns relative to each other-using tools borrowed from network theory. Our results reveal similarities between the skeletal networks of the normal newborn/adult upper limb vs. lower limb, with exception to the shoulder vs. pelvis. However, when muscles are included, the overall musculoskeletal network organization of the upper limb is strikingly different from that of the lower limb, particularly that of the more proximal structures of each limb. Importantly, the obtained data provide further evidence to be added to the vast amount of paleontological, gross anatomical, developmental, molecular and embryological data recently obtained that contradicts the long-standing dogma that the upper and lower limbs are serial homologues. In addition, the AnNA of the limbs of a trisomy 18 human fetus strongly supports Pere Alberch's ill-named \"logic of monsters\" hypothesis, and contradicts the commonly accepted idea that birth defects often lead to lower integration (i.e. more parcellation) of anatomical structures.

The discovery of a living coelacanth specimen in 1938 was remarkable, as this lineage of lobe-finned fish was thought to have become extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features. Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues show the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution.

Key Points Retinoic acid (RA) was first implicated as a signalling molecule on the basis of its teratogenic effects on limb patterning. Studies in chick using treatment with RA or RA receptor antagonists suggested a two-signal model for limb proximodistal patterning in which a proximal RA signal opposes a distal fibroblast growth factor (FGF) signal. Genetic loss-of-function studies in mice confirmed a requirement for distal FGF but not proximal RA in limb proximodistal patterning, thus supporting a one-signal model in which distal FGFs alone control patterning. RA was found to promote forelimb initiation by repressing Fgf8 along the body axis before limb budding. RA–FGF8 antagonism has also been found to be essential for somitogenesis and neurogenesis during body axis extension. RA directly represses caudal Fgf8 through an upstream retinoic acid response element. Genetic loss of RA synthesis has identified several additional roles for RA signalling during organogenesis, including neuronal differentiation in the hindbrain and spinal cord, eye morphogenesis, differentiation of forebrain basal ganglia, heart development and spermatogenesis. The putative role of RA in these developmental processes has been backed up by the identification of target genes that both require RA for normal expression and have nearby functional retinoic acid response elements. Understanding the mechanism of RA-mediated activation and repression during development will benefit efforts to obtain differentiated cell types that are useful in regenerative medicine. Retinoic acid regulates transcription by interacting with nuclear retinoic acid receptors, which bind to retinoic acid response elements near target genes. Recent studies have refined our knowledge of retinoic acid function in the limb, which serves as a paradigm for understanding how it regulates other developmental processes, such as somitogenesis, neuronal differentiation and organogenesis. Retinoic acid (RA) signalling has a central role during vertebrate development. RA synthesized in specific locations regulates transcription by interacting with nuclear RA receptors (RARs) bound to RA response elements (RAREs) near target genes. RA was first implicated in signalling on the basis of its teratogenic effects on limb development. Genetic studies later revealed that endogenous RA promotes forelimb initiation by repressing fibroblast growth factor 8 ( Fgf8 ). Insights into RA function in the limb serve as a paradigm for understanding how RA regulates other developmental processes. In vivo studies have identified RAREs that control repression of Fgf8 during body axis extension or activation of homeobox (Hox) genes and other key regulators during neuronal differentiation and organogenesis.

Nail stem cells (NSCs) reside in the proximal nail matrix, and early nail progenitors undergo Wnt-dependent differentiation into the nail; after amputation, Wnt activation is required for nail and digit regeneration, and amputations proximal to the Wnt-active nail progenitors fail to regenerate, but β-catenin stabilization in the NSC region induces regeneration. Nail controlling digit regeneration Digit-tip regeneration in mice and humans is a remarkable example of mammalian organ regeneration. Nevertheless, this ability is very limited: digits never regenerate when amputated beyond the nail. Mayumi Ito and colleagues provide new insight into this process, by showing that the mechanisms governing nail stem cell differentiation in mice are directly coupled to their ability to orchestrate digit regeneration. Nail progenitors located distal to the nail stem cell region undergo differentiation into nail in a process dependent on Wnt signalling. Wnt signalling activation is also required for nail regeneration and for attracting nerves that promote regeneration of the entire digit after amputation. The authors suggest that nail stem cells might be used for developing new treatments for amputees. The tips of mammalian digits can regenerate after amputation 1 , 2 , like those of amphibians. It is unknown why this capacity is limited to the area associated with the nail 2 , 3 , 4 . Here we show that nail stem cells (NSCs) reside in the proximal nail matrix and that the mechanisms governing NSC differentiation are coupled directly with their ability to orchestrate digit regeneration. Early nail progenitors undergo Wnt-dependent differentiation into the nail. After amputation, this Wnt activation is required for nail regeneration and also for attracting nerves that promote mesenchymal blastema growth, leading to the regeneration of the digit. Amputations proximal to the Wnt-active nail progenitors result in failure to regenerate the nail or digit. Nevertheless, β-catenin stabilization in the NSC region induced their regeneration. These results establish a link between NSC differentiation and digit regeneration, and suggest that NSCs may have the potential to contribute to the development of novel treatments for amputees.

Amniotes show a great diversity of limb phenotypes, including limbs specialized for running, flying, swimming, and digging. Here, we have examined how this diversity is generated during limb development in 13 species using transcriptomics and in situ hybridization. The selected species show evolutionary changes in the number of phalanges and/or loss of claws. We first looked at genes that show cyclical expression during digit development. Significantly, we find that Gdf5 cycles more rapidly in digits developing more phalanges. We identified two novel cyclically expressed genes: Ackr3 and Wnt9a. We also identified a transition point at which phalanx formation stops and claw development begins. We found that this transition point is marked by the downregulation of multiple developmental genes in the phalanx-forming region, and upregulation of claw-related genes. The timing of this transition is conserved, taking place at the same developmental stage in all digits of all species examined—except in the clawless digits of the Chinese soft-shelled turtle, the crocodilians, and birds. We suggest a model based on transcriptional heterochrony, in which the frequency of phalanx formation and the timing of the phalanx–claw transition are evolutionary control points open to natural selection on the phenotype. Furthermore, our model suggests that relaxation of developmental constraints on the timing of the phalanx–claw transition allows the digits to develop more phalanges (hyperphalangy). This is seen in some turtles, crocodilians, and dolphins. More broadly, our findings are consistent with the hypothesis that “hotspots” in otherwise conserved developmental pathways may be targets for evolutionary tinkering.

HoxA genes exhibit central roles during development and causal mutations have been found in several human syndromes including limb malformation. Despite their importance, information on how these genes are regulated is lacking. Here, we report on the first identification of bona fide transcriptional enhancers controlling HoxA genes in developing limbs and show that these enhancers are grouped into distinct topological domains at the sub-megabase scale (sub-TADs). We provide evidence that target genes and regulatory elements physically interact with each other through contacts between sub-TADs rather than by the formation of discreet \"DNA loops\". Interestingly, there is no obvious relationship between the functional domains of the enhancers within the limb and how they are partitioned among the topological domains, suggesting that sub-TAD formation does not rely on enhancer activity. Moreover, we show that suppressing the transcriptional activity of enhancers does not abrogate their contacts with HoxA genes. Based on these data, we propose a model whereby chromatin architecture defines the functional landscapes of enhancers. From an evolutionary standpoint, our data points to the convergent evolution of HoxA and HoxD regulation in the fin-to-limb transition, one of the major morphological innovations in vertebrates.

Butterfly eyespots are beautiful novel traits with an unknown developmental origin. Here we show that eyespots likely originated via cooption of parts of an ancestral appendage gene-regulatory network (GRN) to novel locations on the wing. Using comparative transcriptome analysis, we show that eyespots cluster most closely with antennae, relative to multiple other tissues. Furthermore, three genes essential for eyespot development, Distal-less (Dll), spalt (sal), and Antennapedia (Antp), share similar regulatory connections as those observed in the antennal GRN. CRISPR knockout of cis-regulatory elements (CREs) for Dll and sal led to the loss of eyespots, antennae, legs, and also wings, demonstrating that these CREs are highly pleiotropic. We conclude that eyespots likely reused an ancient GRN for their development, a network also previously implicated in the development of antennae, legs, and wings.

The origin of tetrapods from their fish antecedents, approximately 400 million years ago, was coupled with the origin of terrestrial locomotion and the evolution of supporting limbs. Polypterus is a member of the basal-most group of ray-finned fish (actinopterygians) and has many plesiomorphic morphologies that are comparable to elpistostegid fishes, which are stem tetrapods. Polypterus therefore serves as an extant analogue of stem tetrapods, allowing us to examine how developmental plasticity affects the ‘terrestrialization’ of fish. We measured the developmental plasticity of anatomical and biomechanical responses in Polypterus reared on land. Here we show the remarkable correspondence between the environmentally induced phenotypes of terrestrialized Polypterus and the ancient anatomical changes in stem tetrapods, and we provide insight into stem tetrapod behavioural evolution. Our results raise the possibility that environmentally induced developmental plasticity facilitated the origin of the terrestrial traits that led to tetrapods. The most primitive extant bony fish, Polypterus , exhibits adaptive plasticity for life on land when raised on land rather than in water, suggesting that environmentally induced phenotypic plasticity might have facilitated the macroevolutionary transition to life on land. Best fin forward Bichirs (genus Polypterus ) are primitive ray-finned fish found in Africa — and sometimes in home aquaria — that have functional lungs derived from the swim bladder and powerful pectoral fins that provide support during occasional forays ashore. This study takes Polypterus senegalus as a model for the immediate ancestors of tetrapods and quantifies the anatomical and behavioural changes that occur when these fish are 'terrestrialized'. When raised on land, bichirs lift their heads higher off the ground, deploy their forelimbs closer to the midline and slip around much less often than those raised underwater and prompted to walk ashore for the first time. These observations, together with changes in bone structure and musculature, suggest that some of the postural changes seen in the earliest tetrapods, or rather their immediate antecedents, might have been made in response to the environment and assimilated by developmental plasticity.