A fundamental principle that underlies the anatomical and functional organization of the adult mammalian forebrain is the patterning of the neocortex into distinct areas and the parcellation of the dorsal thalamus (dTh) into nuclei. The developmental patterning of the neocortex into areas, i.e. the process of arealization, is controlled by both intrinsic mechanisms, defined here as regulatory genes that specify positional or area identities of cortical neurons, and extrinsic influences, mainly considered to be area-specific thalamocortical axon (TCA) input, or the information being relayed by it, that arises from dTh nuclei and is established in part by the genetic framework intrinsic to the neocortex. Evidence for the intrinsic genetic regulation of arealization has only begun to emerge over the past few years and thus far has implicated the homeodomain transcription factor EMX2 and the paired-box transcription factor PAX6 in controlling arealization. Less is known about the genetic mechanisms that pattern the dTh into nuclei and specify nuclei-unique properties. We hypothesize that the LIM-homeodomain (LIM-HD) transcription factors LHX2 and LHX9 specify area identities in the cortex and nuclei identities in the dTh through a direct mechanism, based on the known functions of LIM-HD genes, the uniquely graded expression of LHX2 in the neocortex, and the combinatorial expression of LHX2 and LHX9 in subsets of dTh nuclei. We also propose that they indirectly, but critically, influence neocortical arealization by controlling patterning of the dTh into nuclei and specifying properties autonomous to dTh projection neurons that determine the development of their TCA projections to specific neocortical areas, which in turn influence cortical patterning. To study these roles for LHX2 and LHX9, we will employ a range of approaches including conditional gain- and loss-of-function analyses using tissue specific transgene expression and targeted gene inactivation in mice designed to survive to adulthood. We will analyze area- and nuclei-specific phenotypes of cortical and dTh neurons, including expression of markers of identity, specific input and output projections, and the organization of neocortex into areas and dTh into nuclei. The multilevel analyses and alternative strategies proposed will help circumvent potential problems associated with more limited approaches, provide complementary findings to support interpretations, and help establish a hierarchy of regulation of forebrain patterning.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS050646-01
Application #
6861334
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Finkelstein, Robert
Project Start
2004-12-01
Project End
2008-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
1
Fiscal Year
2005
Total Cost
$449,208
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
O'Leary, Dennis Dm; Sahara, Setsuko (2008) Genetic regulation of arealization of the neocortex. Curr Opin Neurobiol 18:90-100
Sahara, Setsuko; Kawakami, Yasuhiko; Izpisua Belmonte, Juan Carlos et al. (2007) Sp8 exhibits reciprocal induction with Fgf8 but has an opposing effect on anterior-posterior cortical area patterning. Neural Dev 2:10
O'Leary, Dennis D M; Chou, Shen-Ju; Sahara, Setsuko (2007) Area patterning of the mammalian cortex. Neuron 56:252-69
O'Leary, Dennis D M; Chou, Shen-Ju; Hamasaki, Tadashi et al. (2007) Regulation of laminar and area patterning of mammalian neocortex and behavioural implications. Novartis Found Symp 288:141-59;discussion 159-64, 276-8
Armentano, Maria; Chou, Shen-Ju; Tomassy, Giulio Srubek et al. (2007) COUP-TFI regulates the balance of cortical patterning between frontal/motor and sensory areas. Nat Neurosci 10:1277-86