| الملخص: |
Craniofacial dysmorphologies are common characteristics of the ciliopathy disease spectrum. Oral malformations, including those affecting the development of the tongue, are among the most common phenotypes of craniofacial ciliopathies. Tongue development requires contributions from cranial neural crest (CNC) cells and mesoderm-derived myoblast. The murine ciliopathic mutant, Kif3a f/f;Wnt1-Cre (Kif3a cKO), which is characterized by loss of primary cilia on CNC cells, exhibits aglossia (loss of a tongue). We found that loss of primary cilia on CNC cells rather than muscle cells results in aglossia. On a cellular level, our data revealed that aglossia in Kif3a cKO embryos is due to a loss of mesoderm-derived muscle precursors. We performed RNA-seq to elucidate the molecular mechanism for this phenotype. We found that Hedgehog (Hh) target genes, the Forkhead box genes, (Foxf1, Foxf2, Foxd1 and Foxd2), were transcriptionally downregulated in Kif3a cKO mandibles. The ratios of Hh effector transcription factors, Gli2 and Gli3 activator (GliA) to repressor (GliR) isoforms were disrupted in Kif3a cKO mutant embryos. Our data showed that the genetic removal of GliA in the CNC cells of wildtype mice recapitulated the aglossia phenotype and downregulated Fox gene expression. Furthermore, our data showed that increasing GliA activity in CNC cells partially rescues the aglossia phenotype and restores Fox gene expression in Kif3a cKO embryos. Together, our data suggests a model in which glossal development is dependent upon primary cilia-dependent GliA activity in CNC cells and the downstream activation of the mandibular Fox genes. |
