Depletion of CTCF induces craniofacial malformations in mouse embryos.

Increasing evidence implicates chromatin structure and epigenetic regulation in various human developmental disorders, including facial abnormalities and intellectual disability. Mutations in CCCTC-binding factor (CTCF) demonstrate its role in craniofacial development, but early lethality precludes the use of Ctcf mutant mice for phenotypic investigations. In this study, we deleted Ctcf specifically in neural crest cells, the multipotent cells that give rise to many structures of the skeleton and connective tissues in the developing head. Although the pharyngeal arches were initially morphologically normal, many of the neural crest cell-derived skeletal and non-skeletal components were truncated in the Wnt1-Cre; Ctcffl/fl mutant mice. The expression level of chondrogenic and osteogenic-related genes were significantly decreased. Our results implicate CTCF in two distinct events in craniofacial development; first, in the regulation of outgrowth and morphogenesis by cell survival and proliferation, and second, in the differentiation of the facial skeleton. Our findings highlight the important contribution of CTCF to craniofacial pathologies. AJTR