The cortex, striatum and pallidum are three key components of cortico-basal ganglia circuits - these circuits regulate limbic, associative and sensorimotor learning. The embryonic basal telencephalon generates subcortical nuclei and cortical interneurons that are required for the function of these circuits. As such, developmental defects of basal telencephalic development can have a profound influence on cognition, emotion and movement. Defects that alter sensorimotor learning can result in motor phenotypes, as exemplified by chorea, tremor and rigidity seen in disorders such as Huntington's disease and Parkinson's disease. Defects that alter limbic and associative learning can result in affective and cognitive defects that may underlie disorders such as Tourette's, Schizophrenia and addiction. The embryonic basal telencephalon primarily consists of the medial ganglionic eminence (MGE);it produces GABAergic and cholinergic projection neurons of the globus pallidus, nucleus basalis and adjacent regions, and GABAergic and cholinergic interneurons that disperse throughout the striatum and cortex. Thus, the basal telencephalon has a central role in generating components of cortical-basal ganglia circuits. An approach to elucidate the genetic underpinnings that regulate the basal telencephalon is to study the function of transcription factors that control the development and function of the neurons that are produced in this region. In this proposal, I describe experiments that study the functions of four transcription factors: Nkx2.
1 (Aim 2), Lhx6 (Aim 3&4), Lhx7/8 (Aims 3&4) and Ldb1 (Aim 5). We hypothesize that combinatorial and unique functions of these four proteins participate in specifying the identity and properties of neurons generated by the embryonic basal telencephalon;the following schema provides the outline of our hypothesis.
Aim 2 tests Nkx2.1 function in SVZ progenitors, pallidal projection neurons, and in the VZ of the most ventral regions of the basal telencephalon.
Aim 3 studies how Lhx6 regulates MGE differentiation.
Aim 4 tests whether Lhx6/Lhx7/8 coordinately regulate MGE development, and Aim 5 tests the function of Ldb1, and whether its phenotypes resemble Lhx6/7(8) mutants. In addition, we will perform fate mapping studies of cells produced in the embryonic basal telencephalon, using Cre-expressing alleles (Aim 1);these alleles will also be useful genetic tools for generating conditional mutants, such as in Aims 2 and 5.

Public Health Relevance

The results from the proposed studies will provide basic information regarding the genetic and developmental mechanisms that control formation of brain regions that control cognition and movement. Disruption of these mechanisms can cause psychiatric and neurological disorders that include mental retardation, autism, schizophrenia, movement disorders and addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH081880-04
Application #
8258337
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Panchision, David M
Project Start
2009-06-20
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$382,388
Indirect Cost
$134,888
Name
University of California San Francisco
Department
Psychiatry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Vogt, Daniel; Hunt, Robert F; Mandal, Shyamali et al. (2014) Lhx6 directly regulates Arx and CXCR7 to determine cortical interneuron fate and laminar position. Neuron 82:350-64
Zhao, Yangu; Flandin, Pierre; Vogt, Daniel et al. (2014) Ldb1 is essential for development of Nkx2.1 lineage derived GABAergic and cholinergic neurons in the telencephalon. Dev Biol 385:94-106

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