title: Decoupling the function of Hox and Shh in developing limb reveals multiple inputs of Hox genes on limb growth.
abstract: Limb 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 Hox-dependent 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.
authors: Laboratory of Genetics and Development, Institut de Recherches Cliniques de Montréal (IRCM, Québec, Canada.
authors: Rushikesh
authors: R
authors: Sheth
authors: Damien
authors: D
authors: Grégoire
authors: Annie
authors: A
authors: Dumouchel
authors: Martina
authors: M
authors: Scotti
authors: Jessica My Trang
authors: JM
authors: Pham
authors: Stephen
authors: S
authors: Nemec
authors: Maria Félix
authors: MF
authors: Bastida
authors: Marian A
authors: MA
authors: Ros
authors: Marie
authors: M
authors: Kmita
mesh_terms: D000483:Alleles; D000818:Animals; D015536:Down-Regulation; D005121:Extremities / Q000196:embryology*; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D005810:Multigene Family; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D014054:Tomography; D000074290:Zinc Finger Protein Gli3; D016207:Cytokines
chemical_list: D051526:Fibroblast Growth Factor 10; D051524:Fibroblast Growth Factor 8; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000074290:Zinc Finger Protein Gli3; C496464:Fgf10 protein, mouse; C496457:Fgf8 protein, mouse; C465571:Gli3 protein, mouse; C486697:Hoxd1 protein, mouse; C465570:Shh protein, mouse; C088144:HoxA protein; C113178:Grem1 protein, mouse; D016207:Cytokines