Sonic Hedgehog Is Essential for First Pharyngeal Arch Development

Abstract

ABSTRACT:The secreted protein sonic hedgehog (Shh) is essential for normal development of many organs. Targeted disruption of Shh in mouse leads to near complete absence of craniofacial skeletal elements at birth, and mutation of SHH in human causes holoprosencephaly (HPE), frequently associated with defects of derivatives of pharyngeal arches. To investigate the role of Shh signaling in early pharyngeal arch development, we analyzed Shh mutant embryos using molecular markers and found that the first pharyngeal arch (PA1) was specifically hypoplastic and fused in the midline, and remaining arches were well formed at embryonic day (E) 9.5. Molecular analyses using specific markers suggested that the growth of the maxillary arch and proximal mandibular arch was severely defective in Shh-null PA1, whereas the distal mandibular arch was less affected. TUNEL assay revealed an increase in the number of apoptotic signals in PA1 of Shh mutant embryos. Ectodermal expression of fibroblast growth factor (Fgf)-8, a cell survival factor for pharyngeal arch mesenchyme, was downregulated in the PA1 of Shh mutants. Consistent with this observation, downstream transcriptional targets of Fgf8 signaling in neural crest-derived mesenchyme, including Barx1, goosecoid, and Dlx2, were also down-regulated in Shh-null PA1. These results demonstrate that epithelial-mesenchymal signaling and transcriptional events coordinated by Shh, partly via Fgf8, is essential for cell survival and tissue outgrowth of the developing PA1. (Pediatr Res 59: 349-354, 2006)

Essential roles of basic helix-loop-helix transcription factors, Capsulin and Musculin, during craniofacial myogenesis of zebrafish

“…Many genetic studies have revealed that endothelin 1 (edn1) and sonic hedgehog (shh) are involved in ventral arch patterning and first arch development, respectively [25,31]. edn1 is expressed throughout the pharyngeal endoderm, mesoderm core and surface ectoderm, and has been taken as a good marker for the ventral mesoderm core [38].…”

“…It was reported that the protein Sonic hedgehog (Shh), secreted partly via activation of Fgf8, is essential for cell survival and tissue outgrowth of the developing first pharyngeal arch [31]. To test whether Hh and Fgf signaling play a role in capsulin activation, we detected the capsulin signals of cyclopamine-and SU5402-treated embryos.…”

Signals and Switches in Mammalian Neural Crest Cell Differentiation

“…Rotations and heterotopic transplantations of axial domains of endoderm affect the orientation of skeletogenic elements and induce ectopic skeletogenic elements, respectively. Shh-null mutant mice have shown the importance of this signal from the endoderm through its role in actively maintaining the expression of key differentiation genes such as Fgf8 and Sox9 in the first pharyngeal arch (Yamagishi et al 2006).…”

Induction of mirror-image supernumerary jaws in chicken mandibular mesenchyme by Sonic Hedgehog-producing cells

“…We have demonstrated so far that Shh can trigger the molecular program for supernumerary lower-jaw development in BA1 territory, knowing that Meckel's cartilage could not develop in the absence of Shh, even though the different elements constituting BA1 (ectoderm, endoderm, mesoderm and NC-derived mesenchyme) were present (Brito et al, 2006;Melnick et al, 2005;Yamagishi et al, 2006). In a second step, we have addressed the issue of whether Shh could instruct other cephalic regions to acquire BA1 properties.…”