The sternum bone lies at the ventral midline of the thorax where it provides a critical attachment for the pectoral muscles that allow the forelimbs to raise the body from the ground. Among tetrapods, sternum morphology is correlated with the mode of locomotion: Avians that fly have a ventral extension, or keel, on their sterna, which provides an increased area for flight muscle attachment. The sternum is fused with the ribs attaching on either side; however, unlike the ribs, the sternal precursors do not originate from the somites. Despite the crucial role of the sternum in tetrapod locomotion, little attention has been given to its acquisition, evolution, and embryological development. We demonstrate an essential role for the T-box transcription factor gene Tbx5 in sternum and forelimb formation and show that both structures share an embryological origin within the lateral plate mesoderm. Consistent with this shared origin and role of Tbx5, sternum defects are a characteristic feature of Holt-Oram Syndrome (OMIM 142900) caused by mutations in TBX5. We demonstrate a link between sternum size and forelimb use across avians and provide evidence that modulation of Tbx5 expression underlies the reduction in sternum and wing size in a flightless bird, the emu. We demonstrate that Tbx5 is a common node in the genetic pathways regulating forelimb and sternum development, enabling specific adaptations of these features without affecting other skeletal elements and can also explain the linked adaptation of sternum and forelimb morphology correlated with mode of locomotion. sternum development | sternum adaptation | sternum defects | Tbx5 T he evolutionary transition from fins to limbs during the colonization of land was a key innovation that enabled extended radiation of the vertebrate clade. Changes in the shape and positioning of the bones of the limb and shoulder girdle during this event have been investigated extensively, but little attention has been given to the acquisition of the sternum, a feature considered characteristic of virtually all terrestrial vertebrates, and which is mandatory for tetrapod locomotion (1).The sternum is a thin flat bone lying at the ventral midline of the thorax that provides a crucial attachment site for the pectoral muscles, allowing the forelimbs to raise the body up from the ground. The sternum forms direct connections with the clavicles and the distal tips of the ribs and, in doing so, strengthens the ribcage and helps protect internal organs such as the heart and lungs. At the caudal extremity, the xiphoid process is an attachment site for the tendons of the diaphragm. Among tetrapods, there is variation in sternal morphology and a clear link between sternum morphology and the mode of locomotion used. This correlation is demonstrated particularly well in avians, which we therefore chose for further study. For example, birds that use their forelimbs (wings) for flight have an adaptation to their sterna in the form of a large ventral extension, known as the keel, which provides an i...
The transcription factor Runx1 plays a pivotal role in hematopoietic stem cell (HSC) emergence, and studies into its transcriptional regulation should give insight into the critical steps of HSC specification. Recently, we identified the Runx1 ؉23 enhancer that targets reporter gene expression to the first emerging HSCs of the mouse embryo when linked to the heterologous hsp68 promoter. Endogenous Runx1 is transcribed from 2 alternative promoters, P1 and P2. Here, we examined the in vivo cis-regulatory potential of these alternative promoters and asked whether they act with and contribute to the spatiotemporal specific expression of the Runx1 ؉23 enhancer. Our results firmly establish that, in contrast to zebrafish runx1, mouse Runx1 promoter sequences do not confer any hematopoietic specificity in transgenic embryos. Yet, both mouse promoters act with the ؉23 enhancer to drive reporter gene expression to sites of HSC emergence and colonization, in a ؉23-specific pattern. (Blood. 2009;113:5121-5124) IntroductionThe transcription factor RUNX1 is a critical regulator of definitive hematopoiesis, and genomic aberrations of the gene encoding RUNX1 are frequently found in human acute leukemia. 1 In the mouse, Runx1 null mutations result in the absence of functional hematopoietic stem cells (HSCs) and definitive progenitors, leading to embryonic lethality. [2][3][4][5][6] During development, Runx1 is first expressed in the emerging hematopoietic system, including definitive HSCs. 7,8 Its highly regulated spatiotemporal expression pattern and pivotal role in HSC emergence prompted us to study its transcriptional regulation, to obtain insight into the molecular mechanisms underlying de novo HSC generation. We recently identified the Runx1 ϩ23 hematopoietic enhancer, located 23.5 kb downstream of the ATG in exon 1. 9 We showed that this ϩ23 enhancer targets reporter gene expression, from a heterologous hsp68 core promoter, to the emerging HSCs and putative HSCfated cells in the mouse embryo, and acts directly downstream of Gata2, SCL, and Ets transcription factors. Whether the ϩ23 enhancer is equally active with the endogenous Runx1 promoters has not been assessed.Runx1 is transcribed from 2 alternative promoters ( Figure 1A), a distal P1 and proximal P2, with the P1 being specific to vertebrates. [10][11][12][13] Both the P1 and P2 promoters were reported to be transcriptionally active in the emerging hematopoietic system of the mouse embryo, at the stages of yolk sac (YS), aortagonad-mesonephros (AGM), and fetal liver (FL) hematopoiesis, with P1-derived transcripts particularly prevalent among enriched FL HSCs. 11,14,15 The P2 promoter was shown to be active in HSC-fated cells 16 and to be critically required for FL hematopoiesis. 17 In vitro transfection assays suggested that neither P1 nor P2 RUNX1 promoter elements harbored tissue-specific cis-regulatory elements. 10 However, in vivo mouse promoter assays have not been reported, and it is therefore not clear to what extent cis-elements elsewhere in the locus are req...
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