Grainyhead-like 2 downstream targets act to suppress epithelial-to-mesenchymal transition during neural tube closure.

The transcription factor grainyhead-like 2 (GRHL2) is expressed in non-neural ectoderm (NNE) andGrhl2loss results in fully penetrant cranial neural tube defects (NTDs) in mice. GRHL2 activates expression of several epithelial genes; however, additional molecular targets and functional processes regulated by GRHL2 in the NNE remain to be determined, as well as the underlying cause of the NTDs inGrhl2mutants. Here, we find thatGrhl2loss results in abnormal mesenchymal phenotypes in the NNE, including aberrant vimentin expression and increased cellular dynamics that affects the NNE and neural crest cells. The resulting loss of NNE integrity contributes to an inability of the cranial neural folds to move toward the midline and results in NTD. Further, we identifiedEsrp1,Sostdc1,Fermt1,Tmprss2andLamc2as novel NNE-expressed genes that are downregulated inGrhl2mutants. Ourin vitroassays show that they act as suppressors of the epithelial-to-mesenchymal transition (EMT). Thus, GRHL2 promotes the epithelial nature of the NNE during the dynamic events of neural tube formation by both activating key epithelial genes and actively suppressing EMT through novel downstream EMT suppressors.

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