Friday, April 19, 2024
4/19/2024
PROJECT SUMMARY Each year in the United States, more than 2,500 babies are born with a cleft palate (CP). CP is caused by disruption of palatogenesis during embryonic development. This proposal aims to delineate critical molecular pathways of palatogenesis, which will lead to development of better methods for diagnosis, treatment and prevention of issues associated with CP. MLL4 (aka KMT2D) is a histone H3-lysine 4 methyltransferase that creates transcriptionally active open chromatin marks. Together with other subunits, such as UTX (aka KDM6A), MLL4 forms a complex (MLL4-C), which functions as an important “epigenetic” transcriptional coactivator that triggers cell type-specific target gene expression. Mutations in the MLL4 gene, as well as the UTX gene, cause the human developmental disorder Kabuki syndrome (KS), which is characterized by craniofacial abnormalities, including CP. We discovered that conditional knockout (cKO) mice with neural crest cell (NCC)-specific deletion of Mll4 develop various KS-like craniofacial phenotypes, including 100% penetrance for CP. These results suggest that the loss of cell autonomous actions of MLL4 in the developing palatal mesenchyme results in CP and other craniofacial structural defects of KS. Thus, we hypothesize that dysregulation of the MLL4-C-dependent gene regulatory program leads to developmental and cellular deficits during palate development, resulting in CP observed in Mll4-cKO mice and human KS. To test our hypothesis, we will pursue two specific aims: Aim 1, to characterize the phenotype of cleft palate defect in Mll4-deficient mice; Aim 2, to define the mechanisms by which Mll4-C regulates palatogenesis. Building on our strong preliminary data from a unique mouse model that develops CP with 100% penetrance, this proposal will greatly advance our understanding of palatogenesis and CP pathogenesis..
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