This grant is aimed at studying the roles of three mouse Nkx homeodomain transcription factors, Nkx2.1, 2.2 and 6.1, in development of the basal plate of the CNS. The genes are expressed in distinct and overlapping expression patterns in the basal plate at different anterior-posterior positions. Work of Rubenstein and others have shown that all three genes are required for aspects of ventral CNS development. Dr. Rubentsein proposes to further study these three genes by carrying out a similar set of experiments for each gene. He will characterize null mutants by marker gene analysis to determine whether specification of certain cell types is altered and analyze cell proliferation, cell death and cell migration in the affected regions. He will complement these studies with gain- of-function studies by ectopically expressing the genes in early chick brain to determine whether they are sufficient to induce ventral cell types. He will also study double mutants to address overlapping gene functions and analyze in more detail expression patterns of these genes later in development and in the adult. A collaborator, Dr. Puelles, will visit the lab twice, for two months each, to help analyze the expression patterns and morphological mutant phenotypes.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-6 (01))
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Wu, Da-Yu
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Pan, Qiuping; Li, Changgong; Xiao, Jing et al. (2004) In vivo characterization of the Nkx2.1 promoter/enhancer elements in transgenic mice. Gene 331:73-82
Flames, Nuria; Long, Jason E; Garratt, Alistair N et al. (2004) Short- and long-range attraction of cortical GABAergic interneurons by neuregulin-1. Neuron 44:251-61
Yun, Kyuson; Garel, Sonia; Fischman, Seth et al. (2003) Patterning of the lateral ganglionic eminence by the Gsh1 and Gsh2 homeobox genes regulates striatal and olfactory bulb histogenesis and the growth of axons through the basal ganglia. J Comp Neurol 461:151-65
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Zhao, Yangu; Marin, Oscar; Hermesz, Edit et al. (2003) The LIM-homeobox gene Lhx8 is required for the development of many cholinergic neurons in the mouse forebrain. Proc Natl Acad Sci U S A 100:9005-10
Marin, Oscar; Plump, Andrew S; Flames, Nuria et al. (2003) Directional guidance of interneuron migration to the cerebral cortex relies on subcortical Slit1/2-independent repulsion and cortical attraction. Development 130:1889-901
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Marin, Oscar; Baker, Joshua; Puelles, Luis et al. (2002) Patterning of the basal telencephalon and hypothalamus is essential for guidance of cortical projections. Development 129:761-73
Marin, O; Yaron, A; Bagri, A et al. (2001) Sorting of striatal and cortical interneurons regulated by semaphorin-neuropilin interactions. Science 293:872-5

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