Abstract
Precise control of self-renewal and differentiation of progenitor cells into the cranial neural crest (CNC) pool ensures proper head development, guided by signaling pathways such as BMPs, FGFs, Shh and Notch. Here, we show that murine Sox2 plays an essential role in controlling progenitor cell behavior during craniofacial development. A “Conditional by Inversion” Sox2 allele (Sox2COIN) has been employed to generate an epiblast ablation of Sox2 function (Sox2EpINV). Sox2EpINV/+(H) haploinsufficient and conditional (Sox2EpINV/mosaic) mutant embryos proceed beyond gastrulation and die around E11. These mutant embryos exhibit severe anterior malformations, with hydrocephaly and frontonasal truncations, which could be attributed to the deregulation of CNC progenitor cells during their epithelial to mesenchymal transition. This irregularity results in an exacerbated and aberrant migration of Sox10+ NCC in the branchial arches and frontonasal process of the Sox2 mutant embryos. These results suggest a novel role for Sox2 as a regulator of the epithelial to mesenchymal transitions (EMT) that are important for the cell flow in the developing head.
Highlights
The head develops from anteriorly located cells of the epiblast
The inverted COIN Sox2 allele (Sox2INV ) is functionally null (Mandalos et al, 2012), as Sox2INV/INV mutants recapitulate the phenotype of Sox2βgeo/βgeo (Avilion et al, 2003a), Sox2βgeo2/βgeo2 (Ekonomou et al, 2005) and Sox2EpINV/βgeo2 (Mandalos et al, 2012) embryos, which die around implantation
Amongst genes of the SoxB1 group (Sox1-3), which are predominantly expressed in the developing central nervous system (CNS) (Collignon et al, 1996; Wood and Episkopou, 1999), Sox3 activity is required for pharyngeal segmentation and for the pharyngeal epithelium to proceed toward craniofacial www.frontiersin.org morphogenesis (Rizzoti and Lovell-Badge, 2007)
Summary
The head develops from anteriorly located cells of the epiblast. These cells form the neuroectoderm that gives rise to the brain and craniofacial structures stemming via epithelial to mesenchymal transitions (EMT). NCCs are induced by interactions between the neuroectoderm and adjacent non-neural ectoderm (Dickinson et al, 1995; Selleck and Bronner-Fraser, 1995). These interactions are orchestrated by a combination of signaling molecules such as Wnt proteins, bone morphogenetic proteins (BMPs) (Liem et al, 1995), fibroblast growth factors (FGFs), retinoic acid and proteins of the Notch pathway (Labonne and Bronner-Fraser, 1998; Aybar et al, 2002; Aybar and Mayor, 2002; Christiansen et al, 2002; Endo et al, 2002; Garcia-Castro et al, 2002; Villanueva et al, 2002; Wu et al, 2003). NCCs delaminate from the dorsal neural tube, migrate along defined territories of the craniofacial complex and differentiate into many cell types, including neurons, glial cells, Schwann cells, melanocytes, and cells of the connective tissue (Ayer-Le Lievre and Le Douarin, 1982)
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