In many ways the cerebral cortex defines us as human beings, and abnormalities of cortical development result in a number of devastating neurologic and neuropsychiatric disorders. The development of cerebral cortex depends on tightly coordinated gene expression that is directed by transcription factors. The long-term objective of this project is to understand the transcriptional control of cortical development. This application focuses on Lhx2, a transcription factor that appears to be essential in multiple stages of cortical development. Our re-analysis of the Lhx2 knockout mouse has identified essential roles for Lhx2 in patterning and formation of virtually all of neocortex and hippocampus. In addition, Lhx2 is likely to have essential roles in late cortical development that cannot be studied in the existing knockout line. The overall goal of this application is to understand the functions of Lhx2 during both early and late cortical development, and to begin identifying components of the Lhx2 genetic hierarchy that controls patterning and formation of the cerebral cortex.
Specific aim 1 will address the early roles of Lhx2 by further characterizing the Lhx2 knockout mouse.
Specific aim 2 will study the bone morphogenetic proteins (BMPS) as potential upstream regulators of Lhx2.
Specific aim 3 will search for downstream targets of Lhx2 by directly testing one candidate and searching for others using the Lhx2 knockout mouse and microarray analysis.
Specific aim 4 will address the late roles of Lhx2 by engineering a conditional knockout line to disrupt Lhx2 in postmitotic cortical neurons. These experiments should provide insight into the transcriptional control of cortical development and help identify other genes that may be responsible for human neurologic and neuropsychiatric brain disorders. The applicant is an MD/PhD who is board-certified in anatomic pathology and neuropathology. He earned his doctoral degree in neuroscience studying transcriptional control of developing glial cells. His mentor is Chris Walsh, who heads a well-funded well-equipped human and mouse cortical development and genetics laboratory. The research career development plan includes learning mouse transgenic technology, with the help of a consultant who runs a local transgenic core facility.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZRG1-MDCN-6 (01))
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Wynne, Debra K
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University of California Irvine
Schools of Medicine
United States
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Mangale, Vishakha S; Hirokawa, Karla E; Satyaki, Prasad R V et al. (2008) Lhx2 selector activity specifies cortical identity and suppresses hippocampal organizer fate. Science 319:304-9
Flanagan, Lisa A; Rebaza, Liza M; Derzic, Stanislava et al. (2006) Regulation of human neural precursor cells by laminin and integrins. J Neurosci Res 83:845-56