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.
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