Grainyhead genes and mammalian neural tube closure

Grainyhead genes encode a family of transcription factors that are well conserved from fly to human. The three mammalian homologues, Grainyhead-like-1, -2, and -3 are expressed in various ectodermal and endodermal cell types during embryonic development and in adult skin. Gene targeting in mice has demonstrated functional roles for Grhl1 and Grhl3 in epidermal integrity and wound healing ability of the epidermis, which appear functionally related to the role of Drosophila grainyhead in production and healing of the epidermal cuticle. Importantly, targeted null mice for Grhl3 also display NTDs, comprising severe spina bifida as well as occasional exencephaly. The chromosomal location of Grhl3 and the finding of NTDs in null embryos suggested that Grhl3 could be allelic with the mouse mutant curly tail, a well known model for NTDs. Expression analysis and transgenic rescue suggest that curly tail is a hypomorphic allele of Grhl3. The functional role and downstream mediators of Grhl3 in neural tube closure are largely unknown. However, the developmental and cellular basis of NTDs in curly tail mutants is well established, involving a proliferation defect in the hindgut endoderm.On this basis, it is possible that Grhl3 has a direct regulatory function in cell proliferation in the hindgut endoderm. Identification of the transcriptional targets of Grhl3 will serve not only to further our understanding of the mechanisms of mammalian neural tube closure, but also to identify potential molecular factors involved in the pathogenesis of NTDs in human.