The primary objective of this proposal is to understand the function of the mouse gene called twist during mammalian embryogenesis. We became interested in twist because it is a homolog of the Drosophila twist gene which is required for mesoderm formation during Drosophila embryogenesis. twist encodes a protein that contains a basic helix-loop-helix motif (B- HLH) and is most likely a transcription factor. Without twist function, Drosophila embryos fail to gastrulate and do not form mesoderm which leads to an embryonic lethality. Mouse twist gene expression is detected in the early mouse embryo and is most abundant in subsets of mesodermal tissue and cephalic neural crest. Thus, we speculated that the mouse twist gene might be a critical regulator of early mouse embryogenesis, perhaps by influencing mesoderm and neural crest differentiation. What is the function of twist during mouse development? One of the most direct ways to address this question and understand gene function is by mutational analysis. Therefore, we have deleted the twist gene by homologous recombination in mouse embryonic stem (ES) cells and have generated germ line chimeric mice. Mice homozygous for the twist deletion exhibit defects in cranial neural tube closure at E9.0 which lead to exencephaly and embryonic lethality. This observation demonstrates that twist function is required for normal neural tube development in mice and provides an animal model for neural tube defects whose precise genetic lesion is known. We propose molecular, genetic, and embryological experiments to understand twist function and regulation during neural tube development. This knowledge should ultimately be useful in understanding the etiology and pathogenesis of neural tube defects, one of the most common developmental abnormalities that afflict man.
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