Abstract

This is an application for the renewal of NIMH Independent Scientist Award K02 MH01046, """"""""Genetic Regulation of Telecephalon Development,"""""""" for John L. R. Rubenstein, M.D., Ph.D. 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. To this end, my laboratory has identified the Dlx genes, which encode a family of homeodomain transcription factors that are candidates for having a central role in striatal development.
The aims of the experiments proposed in this grant application are focused on (1) elucidating the sequence of these genes and their encoded proteins, (2) determining the intracellular location of the DLX proteins, (3) determining the temporal and spatial patterns of expression of the Dlx RNAs and proteins in the prenatal and postnatal forebrain, (4) determining whether the DLX proteins are transcriptional regulators, (5) studying the effect of mutations of these genes on brain development, (6) identifying genes that are regulated by the Dlx genes, and (7) beginning to determine, using ectopic expression experiments, where the Dlx genes are in the genetic hierarchy that regulates development of the forebrain.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research (K02)
Project #
2K02MH001046-06
Application #
2404642
Study Section
Molecular, Cellular, and Developmental Neurobiology Review Committee (MCDN)
Project Start
1993-01-01
Project End
2002-12-31
Budget Start
1998-03-01
Budget End
1998-12-31
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Ghanem, Noel; Yu, Man; Long, Jason et al. (2007) Distinct cis-regulatory elements from the Dlx1/Dlx2 locus mark different progenitor cell populations in the ganglionic eminences and different subtypes of adult cortical interneurons. J Neurosci 27:5012-22
Cobos, Inma; Broccoli, Vania; Rubenstein, John L R (2005) The vertebrate ortholog of Aristaless is regulated by Dlx genes in the developing forebrain. J Comp Neurol 483:292-303
Jones, Edward G; Rubenstein, John L R (2004) Expression of regulatory genes during differentiation of thalamic nuclei in mouse and monkey. J Comp Neurol 477:55-80
Huffman, Kelly J; Garel, Sonia; Rubenstein, John L R (2004) Fgf8 regulates the development of intra-neocortical projections. J Neurosci 24:8917-23
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
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
Rubenstein, J L R; Merzenich, M M (2003) Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2:255-67
Tran, Phu V; Lee, Martin B; Marin, Oscar et al. (2003) Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons. Mol Cell Neurosci 22:441-53
Blackshear, Perry J; Graves, Joan P; Stumpo, Deborah J et al. (2003) Graded phenotypic response to partial and complete deficiency of a brain-specific transcript variant of the winged helix transcription factor RFX4. Development 130:4539-52
Bishop, Kathie M; Garel, Sonia; Nakagawa, Yasushi et al. (2003) Emx1 and Emx2 cooperate to regulate cortical size, lamination, neuronal differentiation, development of cortical efferents, and thalamocortical pathfinding. J Comp Neurol 457:345-60

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