Language is a specialized mental faculty that enables humans to arrange and communicate thoughts through the use of different modalities such as sounds or symbols. Numerous studies have shown that several regions in the neural system might be responsible for the processing and production of speech and language. However, studies on the development and organization of the complex underlying neuronal circuitry at the cellular and molecular levels have been technically challenging. Recent reports by other groups and preliminary results generated in my laboratory provided us with an opportunity to undertake such an analysis. We have identified a small population of cortical pyramidal neurons present in the human fetal speech-related cortical region. These neurons are uniquely identified by the combinatorial expression of Forkhead Box P2 (FOXP2), haploinsufficiency in which can lead to a severe speech disorder, Nitric Oxide Synthase 1 (NOS1), and ZNF312, a novel layer V-specific transcription factor. Based on the areal and laminar position of these neurons, as well as their gene expression, we hypothesize that they are a central component in the circuitry that mediates language processing and speech production. In this grant application, we propose to characterize the functional roles of transcription factors FOXP2 and ZNF312 in the development, refinement and maintenance of that corticostriatal and corticothalamic circuits. In the first specific aim of this proposal, we propose to analyze the organization and distribution of FOXP2-positive corticofugal projections in the primate ventrolateral frontal cortex. In the second aim, we propose to determine the role of FOXP2 in the refinement and maintenance of corticostriatal and corticothalamic projections. In the third specific aim, we propose to determine the role of zinc finger protein, ZNF312, in the formation and corticostriatal and corticothalamic projections. The elucidation of how FOXP2 and ZNF312 may regulate development of neural pathways involved in spoken language as outlined in this proposal will help in understanding normal brain development and the neurobiological foundations of speech and language. This research may further facilitate the identification of additional disease genes and the development of new therapeutic strategies for the treatment of speech and motorrelated disorders ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS054273-01A1
Application #
6988251
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Babcock, Debra J
Project Start
2005-07-01
Project End
2009-04-30
Budget Start
2005-07-01
Budget End
2006-04-30
Support Year
1
Fiscal Year
2005
Total Cost
$378,094
Indirect Cost
Name
Yale University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Shibata, Mikihito; Gulden, Forrest O; Sestan, Nenad (2015) From trans to cis: transcriptional regulatory networks in neocortical development. Trends Genet 31:77-87
Ercan-Sencicek, A Gulhan; Jambi, Samira; Franjic, Daniel et al. (2015) Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans. Eur J Hum Genet 23:165-72
Robichaux, Michael A; Chenaux, George; Ho, Hsin-Yi Henry et al. (2014) EphB receptor forward signaling regulates area-specific reciprocal thalamic and cortical axon pathfinding. Proc Natl Acad Sci U S A 111:2188-93
Miller, Jeremy A; Nathanson, Jason; Franjic, Daniel et al. (2013) Conserved molecular signatures of neurogenesis in the hippocampal subgranular zone of rodents and primates. Development 140:4633-44
Li, Hong; Fertuzinhos, Sofia; Mohns, Ethan et al. (2013) Laminar and columnar development of barrel cortex relies on thalamocortical neurotransmission. Neuron 79:970-86
Han, Wenqi; Sestan, Nenad (2013) Cortical projection neurons: sprung from the same root. Neuron 80:1103-5
Shim, Sungbo; Kwan, Kenneth Y; Li, Mingfeng et al. (2012) Cis-regulatory control of corticospinal system development and evolution. Nature 486:74-9
Kwan, Kenneth Y; Lam, Mandy M S; Johnson, Matthew B et al. (2012) Species-dependent posttranscriptional regulation of NOS1 by FMRP in the developing cerebral cortex. Cell 149:899-911
Kwan, Kenneth Y; Sestan, Nenad; Anton, E S (2012) Transcriptional co-regulation of neuronal migration and laminar identity in the neocortex. Development 139:1535-46
State, Matthew W; Sestan, Nenad (2012) Neuroscience. The emerging biology of autism spectrum disorders. Science 337:1301-3

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