Primary cilia are microtubule-based organelles protruding from the surface of mammalian cells, which function as hubs for transducing both biochemical signals (such as Hedgehog) and mechanical force. Defects in cilia are associated with a group of genetic disorders called ciliopathies that disrupt the normal development of multiple organs, including the craniofacial skeleton. One such example is Ellis–van Creveld (EvC) syndrome, a ciliopathy mainly caused by mutations in EVC (EvC ciliary complex subunit1), a key component of the primary cilium essential for the transduction of Hedgehog signaling. Patients with EvC syndrome exhibit a wide spectrum of clinical phenotypes related to multisystemic involvement, including oral defects such as malformations of the teeth, oral vestibule, and ectopic frenula. These distinctive oral defects play a crucial role in the initial diagnosis. The oral vestibule and associated frenula are formed from an embryonic structure, known as the vestibular lamina (VL), which forms closely associated with the dental lamina that forms the teeth. Here we reveal the developmental mechanisms underlying the oral defects in EvC syndrome using Evc knockout mice. Evc mutants exhibited defects in teeth, frenula, and the oral vestibule, mirroring the oral traits of patients with EvC syndrome. A defect in proliferation, and downregulation of Gli1 and Sostdc1 during initial outgrowth, led to a shortened VL, although postnatal differentiation and opening of the VL was normal. In some mutants, the VL branched and formed an ectopic tooth germ, which could be partially mimicked by the overexpression of Wnt signaling in the VL. Notably, we observed both upregulation and downregulation of Gli1 expression, which was time and tissue specific, suggesting dynamic dysregulation of the normal GLIActivator and GLIRepressor balance. These findings provide novel insights into the underlying etiology of EvC syndrome and other ciliopathies and emphasize that structures developing in close proximity can exhibit divergent responses to the same mutation.
Qiu et al. (Mon,) studied this question.