Regulation of geminin expression in embryonic ectoderm

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DESCRIPTION (provided by applicant): Our long-term objective is to dissect the molecular circuitry that underlies cell fate determination in the neurectoderm during early vertebrate embryogenesis. Information obtained in these studies may ultimately impact multiple human health issues, including our ability to manipulate embryonic stem cells for human therapies in the nervous system, and our understanding of the molecular basis of birth defects, including holoprosencephaly and spina bifida. These birth defects are among the most common congenital malformations in humans. Our general strategy is to focus upon a group of genes that act as primary effectors of neural fate during early embryogenesis. Expression of these genes in the future neural plate represents the earliest transcriptional response of ectoderm to neural-inducing signals from adjacent cells. This expression demarcates the embryonic ectoderm into neural versus non-neural territories. It is not known how this transcription arises or which molecular determinants and signaling pathways are direct regulators. Here, we have used a manipulatable transgenic Xenopus embryo system to reconstitute cis-regulatory controls underlying the early neural expression of one such gene, geminin. We show that 5' regulatory sequences from geminin recapitulate its expression and respond to inductive signals in the same manner as the endogenous gene. We propose use of several approaches to identify discrete cis-elements and protein complexes that directly control the onset of geminin's initial neural-specific transcriptional program, including injection and transgenic methodologies in vivo and various molecular methodologies in vitro. These studies should fill a critical gap in our understanding of the molecular basis of neural cell fate determination.