Transcriptional control of neural crest development by MEF2C.

摘要

MEF2 transcription factors are well-established regulators of cardiac and skeletal muscle development. We have identified a novel role for MEF2C in the neural crest where its function is required for craniofacial development. Conditional inactivation of Mef2c in the neural crest results in severe defects in multiple bones of the craniofacial skeleton, leading to neonatal lethality due to upper airway obstruction.;Here I have identified the molecular pathways involving MEF2C during craniofacial development. I show that MEF2C directly regulates Dlx5 and Dlx6 expression in the craniofacial mesenchyme through a novel branchial arch-specific enhancer in the Dlx5/6 locus. In addition, MEF2C and Dlx5 transcriptionally synergize on the Dlx5/6 enhancer, suggesting that Dlx5 is not only a downstream target but also a cofactor of MEF2C during craniofacial development. I present strong evidence to show that MEF2C and Dlx5 can physically interact through their DNA binding domains. In addition to this transcriptional synergy and physical association, MEF2C and Dlx5 genetically interact. Heterozygosity at either locus (Dlx5/6+/- or Mef2c +/-) results in viable mice with no obvious phenotype, but heterozygosity at both loci (Dlx5/6+/-;Mef2c +/-) results in perinatal lethality. Dlx5/6 +/-;Mef2c+/- mice exhibit a significant cleft of the posterior palate, caused due to a delay in the elevation and closure of palatal shelves, suggesting that MEF2C and Dlx5/6 may coregulate palatogenesis. Preliminary evidence suggests that this palate defect may be due to a delay or defect in osteogenic differentiation within the palatal shelves.;In addition to craniofacial defects, neural crest-specific knockouts of Mef2c also show reduced expression of several melanocyte genes during development, and a significant reduction in the number of melanocytes at birth. We have strong evidence to suggest that MEF2C is a direct transcriptional target and cofactor of Sox10 in the melanocyte lineage.;Taken together, the results presented in this thesis identify two neural crest lineages, the craniofacial skeleton and melanocytes, in which MEF2C cooperates with lineage-specific transcription factors to potentiate cell fate decisions. These data also lend significant insight into our understanding of the transcriptional complexes and signaling pathways facilitating the development of these lineages.