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 #
5K02MH001046-09
Application #
6343672
Study Section
Molecular, Cellular, and Developmental Neurobiology Review Committee (MCDN)
Project Start
1993-01-01
Project End
2002-12-31
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
9
Fiscal Year
2001
Total Cost
$100,845
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
094878337
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
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
Storm, Elaine E; Rubenstein, John L R; Martin, Gail R (2003) Dosage of Fgf8 determines whether cell survival is positively or negatively regulated in the developing forebrain. Proc Natl Acad Sci U S A 100:1757-62
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
Puelles, Luis; Rubenstein, John L R (2003) Forebrain gene expression domains and the evolving prosomeric model. Trends Neurosci 26:469-76
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

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