There is abundant evidence to suggest that neuropsychiatric disorders such as schizophrenia and autism are caused in many cases by genetic abnormalities that affect development and function of forebrain neural systems involved in cognition and emotion. The largest structures of the forebrain are the cerebral cortex and the striatum; both have been implicated as having a role in neuropsychiatric disorders. The goal of my research is to understand how genes regulate development of the striatum and other forebrain structures. To this end, my laboratory has studied the Dlx genes, which encode a family of homeodomain transcription factors. There are four known Dlx genes that are expressed in the embryonic forebrain. This application is for renewal of a grant in which I proposed to study the function of Dlx-1 and -2 using gene targeted mutagenesis in mice (1 R01 MH51561-01A1). We have accomplished the aims set out in that grant and have discovered that mice lacking both Dlx-1 and -2 have a severe abnormality of basal ganglia differentiation.
The aims of the experiments proposed in this grant application are focused on (1) fully characterizing the phenotype of the Dix-1, Dlx-2 and Dlx-1 and -2 mutant mice; (2) identifying and characterizing genes that are dysregulated in the Dlx-mutant mice; (3) studying the genetic interactions of the Dlx, Gsh and Mash genes; and (4) making mutations in Dlx-5, Dlx-6 and Dlx-5 and -6.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH051561-06
Application #
6185952
Study Section
Molecular, Cellular, and Developmental Neurobiology Review Committee (MCDN)
Project Start
1994-09-30
Project End
2003-05-31
Budget Start
2000-06-01
Budget End
2001-05-31
Support Year
6
Fiscal Year
2000
Total Cost
$190,106
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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
Andrews, Gracie L; Yun, Kyuson; Rubenstein, John L R et al. (2003) Dlx transcription factors regulate differentiation of dopaminergic neurons of the ventral thalamus. Mol Cell Neurosci 23:107-20
Garel, Sonia; Huffman, Kelly J; Rubenstein, John L R (2003) Molecular regionalization of the neocortex is disrupted in Fgf8 hypomorphic mutants. Development 130:1903-14
Long, Jason E; Garel, Sonia; Depew, Michael J et al. (2003) DLX5 regulates development of peripheral and central components of the olfactory system. J Neurosci 23:568-78
Marin, Oscar; Rubenstein, John L R (2003) Cell migration in the forebrain. Annu Rev Neurosci 26:441-83
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
Garel, Sonia; Yun, Kyuson; Grosschedl, Rudolf et al. (2002) The early topography of thalamocortical projections is shifted in Ebf1 and Dlx1/2 mutant mice. Development 129:5621-34
Yun, Kyuson; Fischman, Seth; Johnson, Jane et al. (2002) Modulation of the notch signaling by Mash1 and Dlx1/2 regulates sequential specification and differentiation of progenitor cell types in the subcortical telencephalon. Development 129:5029-40
Anderson, Stewart A; Kaznowski, Christine E; Horn, Carrie et al. (2002) Distinct origins of neocortical projection neurons and interneurons in vivo. Cereb Cortex 12:702-9
Bagri, Anil; Marin, Oscar; Plump, Andrew S et al. (2002) Slit proteins prevent midline crossing and determine the dorsoventral position of major axonal pathways in the mammalian forebrain. Neuron 33:233-48

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