Creation of CTIP1 and CTIP2 Null Mice

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The objective of this proposal (single term, 12 months) is to create mice null for expression of COUP TF-Interacting Proteins 1 and 2 (CTIP1 and CTIP2, respectively) toward the goal of elucidating the role of each protein during embryogenesis and in the adult animal. This sabbatical period will also afford an opportunity for the PI to develop expertise in the techniques associated with genomic manipulations in the mouse including homologous recombination in and culture of embryonic stem cells, blastocyst injection and genotyping/analysis of the resultant mice. The PI's goal is to establish such technology on the campus of Oregon State University, which is currently devoid, but in great need, of a facility for creation of knock-out and transgenic animals. CTIP1 and CTIP2 represent two members of a novel family of C2H2 zinc finger proteins that were isolated in a yeast two-hybrid screen conducted to identify proteins capable of interaction with members of the COUP-TF family of orphan nuclear receptors. Both CTIP1 and CTIP2 are highly expressed in brain, as are all members of the COUP-TF family of proteins. CTIP1 has been examined in detail and was found to harbor autonomous transcriptional regulatory domains and to potentiate the transcriptional repression activity of ARP1, a COUP-TF family member, in mammalian cells in a manner that was not sensitive to reversal by the histone deacetylase inhibitor, trichostatin A. This finding suggests that transcriptional repression mediated by ARP1.CTIP1 complexes in mammalian cells may be mechanistically distinct from that of other nuclear receptors. The work described herein will facilitate elucidation of the function of the CTIP proteins in an organismal context as well as definition of the underlying molecular mechanisms by which COUP-TF family members, acting through this novel family Of C2H2 zinc finger proteins, may exert transcriptional regulatory activity during embryogenesis and in the adult animal.