Early embryogenesis in CHDFIDD mouse model reveals facial clefts and altered craniofacial neurogenesis

Congenital heart defects, facial dysmorphism and intellectual development disorder (CHDFIDD) is associated with mutations in CDK13 gene which encodes a transcription regulating Cyclin-dependent kinase 13 (CDK13). Here we analyzed early embryonic stages of CHDFIDD mouse models with hypomorphic mutation in Cdk13 gene with very similar phenotypic manifestations plus cleft lip/palate and knockout of Cdk13 which exhibits robust phenotype with midfacial cleft. Cdk13 is strongly expressed in the mouse embryonic craniofacial structures, namely in the forebrain, nasal epithelium and maxillary mesenchyme. In vitro, CDK13 protein is located not only in nuclear region but also in the cellular protrusions in cultured mesenchymal cells and cells isolated from dorsal root ganglia. In Cdk13-deficient embryos, we found hypoplastic branches of the trigeminal nerve including maxillary branch and additionally we detected significant gene expression changes of molecules involved in neurogenesis (Mef2c, Pou4f1, Sod1, Cdk5rap2, Nrcam) within the developing palatal shelves. Key palate-associated molecules (Msx1 and Meis2) were downregulated during early craniofacial development in mutant embryos. These results demonstrate the role of CDK13 in regulation of facial morphogenesis and also growth of craniofacial peripheral nerves.

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