Abstract
Many complex molecular interactions are involved in the process of craniofacial development. Consequently, the network is sensitive to genetic mutations that may result in congenital malformations of varying severity. The most common birth anomalies within the head and neck are orofacial clefts (OFCs) and prognathism. Orofacial clefts are disorders with a range of phenotypes such as the cleft of the lip with or without cleft palate and isolated form of cleft palate with unilateral and bilateral variations. They may occur as an isolated abnormality (nonsyndromic—NSCLP) or coexist with syndromic disorders. Another cause of malformations, prognathism or skeletal class III malocclusion, is characterized by the disproportionate overgrowth of the mandible with or without the hypoplasia of maxilla. Both syndromes may be caused by the presence of environmental factors, but the majority of them are hereditary. Several mutations are linked to those phenotypes. In this review, we summarize the current knowledge regarding the genetics of those phenotypes and describe genotype–phenotype correlations. We then present the animal models used to study these defects.
Highlights
The development of craniofacial structures is a complex process regulated by several signaling pathways including bone morphogenetic proteins (BMPs), Sonic hedgehog (Shh), and Wnt [1,2]
PCP is regulated by small GTPases such as RAC1, and a recent study showed that levels of this protein were regulated in the palatal mesenchyme prior to palatal shelf elevation; the overexpression of Rac1 was found to lead to disruptions in palatal shelf reorientation [1]
The data show that the SHH expressed in oropharyngeal epithelium antagonizes BMP signaling and patterns the oral–aboral axis of the mandibular arch [25]
Summary
The development of craniofacial structures is a complex process regulated by several signaling pathways including bone morphogenetic proteins (BMPs), Sonic hedgehog (Shh), and Wnt [1,2]. PCP is regulated by small GTPases such as RAC1, and a recent study showed that levels of this protein were regulated in the palatal mesenchyme prior to palatal shelf elevation; the overexpression of Rac was found to lead to disruptions in palatal shelf reorientation [1] These data support the role of the Wnt–PCP pathway during palatogenesis. Mice null for Jag, Irf, Grhl, or Fgf have displayed cleft palates and abnormalities in the fusion process [17,18,19,20] These data, together with analyses of the double Irf6/Jag and Irf6/p63 mutants, have revealed a molecular network involving Fgf10/Fgfr and Jag2/Notch signaling regulating the process of periderm formation, a monolayer of flat epithelial cells that covers the internal and external surfaces of the embryo during development [21]. Placing these palates in explant cultures, even with direct contact, fails to rescue the fusion, potentially because Tgfβ3−/− embryos have palatal shelves that are still covered with persistent peridermal cells
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