Hox genes regulate the onset of <i>Tbx5</i> expression in the forelimb

Minguillón, Carolina; Nishimoto, Satoko; Wood, Sophie; Vendrell, Elisenda; Gibson‐Brown, Jeremy J.; Logan, Malcolm

doi:10.1242/dev.084814

Cited by 66 publications

(106 citation statements)

References 52 publications

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“…Activation of Fgf10 expression in the presumptive forelimb field of the LPM relies on Tbx5 (Agarwal et al, 2003;Rallis et al, 2003). Recently, analysis of Tbx5 regulation identified Hox proteins from paralogous group 4 and 5 as regulators of Tbx5 expression in the LPM (Minguillon et al, 2012). Despite the absence of Hoxd4, Hoxa4 and Hoxa5 in the LPM of Hox(A;D)null embryos, we did not detect clear modification of Fgf10 expression in the LPM (not shown), suggesting that the absence of HoxA;D genes in the LPM has minor, if any, impact on the Tbx5-mediated regulation of Fgf10.…”

Section: Multiple Inputs Of Hox Genes On the Epithelialmesenchymal Inmentioning

confidence: 99%

Decoupling the function of Hox and Shh in developing limb reveals multiple inputs of Hox genes on limb growth

et al. 2013

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SUMMARYLimb development relies on an exquisite coordination between growth and patterning, but the underlying mechanisms remain elusive. Anterior-posterior and proximal-distal specification initiates in early limb bud concomitantly with the proliferative expansion of limb cells. Previous studies have shown that limb bud growth initially relies on fibroblast growth factors (FGFs) produced in the apical ectodermal ridge (AER-FGFs), the maintenance of which relies on a positive-feedback loop involving sonic hedgehog (Shh) and the BMP antagonist gremlin 1 (Grem1). The positive cross-regulation between Shh and the HoxA and HoxD clustered genes identified an indirect effect of Hox genes on the maintenance of AER-FGFs but the respective function of Shh and Hox genes in this process remains unknown. Here, by uncoupling Hox and Shh function, we show that HoxA and HoxD genes are required for proper AER-FGFs expression, independently of their function in controlling Shh expression. In addition, we provide evidence that the Hoxdependent control of AER-FGF expression is achieved through the regulation of key mesenchymal signals, namely Grem1 and Fgf10, ensuring proper epithelial-mesenchymal interactions. Notably, HoxA and HoxD genes contribute to both the initial activation of Grem1 and the subsequent anterior expansion of its expression domain. We propose that the intricate interactions between Hox genes and the FGF and Shh signaling pathways act as a molecular network that ensures proper limb bud growth and patterning, probably contributing to the coordination of these two processes.

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Section: Multiple Inputs Of Hox Genes On the Epithelialmesenchymal Inmentioning

confidence: 99%

Decoupling the function of Hox and Shh in developing limb reveals multiple inputs of Hox genes on limb growth

et al. 2013

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“…Several additional regulators of anterior limb patterning have been identified in human disease syndromes as well as in mouse mutants. Forelimb defects similar to those seen in Hox5 mutants have been identified in patients with HOS caused by Tbx5 mutations (32)(33)(34)(35)(36), and Hox genes have been reported to be capable of driving Tbx5 expression (46), OS caused by Sall4 mutations (29,30), TownesBrocks syndrome caused by Sall1 mutations (31,47) and SaethreChotzen syndrome caused by Twist1 mutations, which also show limb phenotypes in mutant mice (48)(49)(50). Mutations of both the human and mouse limb enhancer of Shh, ZRS (7,18,19,24), and human multiple congenital anomaly/mental retardation syndromes caused by mutations of Plzf, as well as loss-of-function mutations in Plzf in mice (37,39), lead to similar phenotypes.…”

Section: Inactivation Of Hox5 Paralogous Group Genes Results In Anteriormentioning

confidence: 91%

Hox5 interacts with Plzf to restrict Shh expression in the developing forelimb

Hrycaj

McIntyre

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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To date, only the five most posterior groups of Hox genes, Hox9-Hox13, have demonstrated loss-of-function roles in limb patterning. Individual paralog groups control proximodistal patterning of the limb skeletal elements. Hox9 genes also initiate the onset of Hand2 expression in the posterior forelimb compartment, and collectively, the posterior HoxA/D genes maintain posterior Sonic Hedgehog (Shh) expression. Here we show that an anterior Hox paralog group, Hox5, is required for forelimb anterior patterning. Deletion of all three Hox5 genes (Hoxa5, Hoxb5, and Hoxc5) leads to anterior forelimb defects resulting from derepression of Shh expression. The phenotype requires the loss of all three Hox5 genes, demonstrating the high level of redundancy in this Hox paralogous group. Further analyses reveal that Hox5 interacts with promyelocytic leukemia zinc finger biochemically and genetically to restrict Shh expression. These findings, along with previous reports showing that point mutations in the Shh limb enhancer lead to similar anterior limb defects, highlight the importance of Shh repression for proper patterning of the vertebrate limb.

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“…Thus, a cis-regulatory study of an intronic enhancer in the mouse tbx5 gene demonstrates that its expression in the forelimb bud is driven by hox genes of paralog groups 4 and 5 ( Fig. 4.1(D); Minguillon et al, 2012). These Hox factors could also activate the tbx5 reporter ectopically in electroporation experiments in the chick embryo.…”

Section: Initial Specification Of the Forelimb Bud In Amniotesmentioning

confidence: 90%