The ability to accomplish and develop complex cognitive and motor tasks depends on the accuracy and intricacy of synaptic connections both within the cerebral cortex and between the cortex and other regions of the brain. Axonal projections of excitatory projection (pyramidal) neurons constitute the motor output of the entire cortex and directly influence behavior. Molecular mechanisms regulating the molecular identity and connectivity of distinct cortical projection neurons are being unraveled. Our goal is to identify mechanisms that are important for the migration, molecular identity and connectivity of pyramidal neurons, and to investigate their functional roles using a variety of molecular and genetic approaches. Our published and preliminary studies, supported by this grant in the last four years, have functionally characterized several genes encoding transcription factors and axon guidance that control different aspect of cortical projection neuron development, such as their molecular identity, laminar position, dendritic arborization, and axonal projections. In this application we intend to further characterize the cellular and molecular mechanisms by which some of these genes function. Specifically, the proposed experiments are designed to determine how Sox5 controls early-born subcortical projection neurons migration to their proper laminar positions and extend axonal projections (Aim1);how layer-specific expression of Fezf2 and subsequently the molecular identity of projection neurons are controlled cell-intrinsically by upstream transcriptional regulators (Aim2);and how formation of axonal connections with subcortical targets, such as the thalamus, controls gene expression cell-extrinsically in cortical projection neurons during late embryogenesis (Aim3).

Public Health Relevance

The identification of genes and molecular mechanisms involved in the formation and maturation of the cortical circuits as outlined in this proposal will help in understanding normal human brain development and plasticity as well as the neurobiological foundations of developmental and cognitive brain disorders such as mental retardation, schizophrenia, autism, and language impairment. This research may further facilitate the identification of disease genes and the development of new therapeutic strategies for the treatment of these disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Babcock, Debra J
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Yale University
Schools of Medicine
New Haven
United States
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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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