Defective Forebrain Development in Mutant Mice

University Of California, San Francisco, San Francisco CA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Mutations that disrupt forebrain development provide a powerful tool for dissecting the mechanisms that regionalize the neural plate and establish neuronal identity. Oto is a mouse mutant in which anterior identity in the neural plate is not established properly. We have mapped the oto mutation to a region of 284 kb on mouse chromosome 1 and identified three candidate genes in the region. One of the candidates is expressed in the axial mesendoderm and its expression is reduced in oto embryos. Study of oto is directed at identifying the causative mutation. [unreadable] Another mutant mouse, open-mind (om), has defects in two signaling centers that pattern the anterior neural plate, the notochord and the anterior neural ridge. We have identified a mutation in the RERE gene as the basis of the om phenotype. RERE is related to both the atrophin-1 gene, which is mutated in patients suffering from Dentato-rubro-pallidal-luysian atrophy, and to MTA-2, the product of which is an obligate subunit of a histone deacetylase complex. Early expression of RERE is widespread but becomes increasingly restricted to neurons by mid-gestation. Early lethality in mutant embryos and widespread expression of the gene prevent a full characterization of its developmental roles. [unreadable] We will use tissue-specific knockout mutations to explore the requirement for RERE function in the establishment of signaling centers and in neurons. We will explore the relationship between the function of RERE and atrophin-1 during early development. Finally we will examine the known and predicted protein associates of the RERE gene product to determine the proximal effects of its loss [unreadable] [unreadable]