136 - Non-cell Autonomous Function of Mediator Complex Subunit, Med23 in Endothelial Cells Regulates Craniofacial Development

Poster Board Number: 136
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Abstract Body : Craniofacial development is a complex process that requires the coordinated integration of all three germ layers. Ectoderm derived neural crest cells (NCC) give rise to most of the craniofacial cartilage and bone as well as cranial ganglia, and their development is regulated by intrinsic tissue specific transcription and signaling factors in concert with molecular cues from surrounding tissues. However, this interdependency between NCC and surrounding tissues during craniofacial development is not yet fully understood and may contribute to the prevalence of congenital craniofacial disorders in humans. In a phenotype driven forward genetics screen aimed at identifying novel regulators of craniofacial development, we identified an embryonic lethal mouse mutant, snouty, which exhibits malformation of the craniofacial prominences and vascular network. The snouty mutation was mapped to a single nucleotide change in Med23, which encodes a protein subunit of the global transcription co-factor complex, Mediator. We, therefore generated endothelial cell-specific mouse mutants of Med23, and Med23fx/fx;Tek-Cre to study the vascular defects due to the absence of Med23. Surprisingly, along with vascular anomalies of hemorrhage and edema, Med23fx/fx;Tek-Cre mutants display anomalies in osteogenesis in the craniofacial region. Further, Med23fx/fx;Tek-Cre mutants present with cleft palate, micrognathia and ocular anomalies. Consistent with the osteogenesis defect phenotype, osteogenesis regulator, Runx2 is downregulated in Med23fx/fx;Tek-Cre mice, which prevents the differentiation of NCC into bone. Both cleft palate and ocular anomaly phenotypes of Med23fx/fx;Tek-Cre mice arise due to defect in vasculogenesis, leading us to investigate the molecular changes in the palatal epithelium, retina and the vasculature surrounding these tissues. Our data supports a non-cell autonomous requirement for Med23 in neural crest cell and craniofacial development and reveals the interdependency of NCC and endothelial cell interactions during craniofacial morphogenesis. This work is supported by the Stowers Institute for Medical Research, Postdoctoral fellowship from American Association for Anatomy and K99 from NIDCR.