Human neurological disorders, such as mental retardation, cerebral palsy and some forms of epilepsy are usually caused by abnormalities in development of the brain. The goal of the research described in this grant application is to begin to understand some of the genetic mechanisms that control development of the cerebral cortex, which is the largest component of the human brain. The hypothesis behind these experiments is that regional specification of, and, the differentiation within the cerebral cortex, is in part controlled by transcriptional regulators whose expression and function is independent of synaptic influences. Candidates for several of the genes that participate in this regulatory network have recently been identified by this research group as well as by scientists in several other laboratories. Many of these candidate genes encode proteins containing a homeodomain. These genes include members of the Otx and Emx families. Recently, a novel candidate transcription factor was discovered, related to the Brachyury gene, that is named Tbr-1. The work proposed in this application will focus on the role of the Tbr-1 and Emx-1 genes in the development of the cerebral cortex. The work is divided into three parts: (A) Structural analysis of the Tbr-1, Tbr-2 and Emx-1 genes; (B) An analysis of the organization of the cerebral cortex in the embryonic, fetal and postnatal mouse, by studying the expression patterns of Tbr-1, Tbr-2, Emx-1 and other genes; (C) Functional analysis of the Tbr-1, Tbr-2 and Emx-1 genes by making null alleles using gene replacement methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034661-03
Application #
2735679
Study Section
Neurology C Study Section (NEUC)
Program Officer
Broman, Sarah H
Project Start
1996-09-01
Project End
2000-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Fazel Darbandi, Siavash; Robinson Schwartz, Sarah E; Qi, Qihao et al. (2018) Neonatal Tbr1 Dosage Controls Cortical Layer 6 Connectivity. Neuron 100:831-845.e7
Liu, Jinyue; Reggiani, Jasmine D S; Laboulaye, Mallory A et al. (2018) Tbr1 instructs laminar patterning of retinal ganglion cell dendrites. Nat Neurosci 21:659-670
Dickel, Diane E; Ypsilanti, Athena R; Pla, Ramón et al. (2018) Ultraconserved Enhancers Are Required for Normal Development. Cell 172:491-499.e15
Ypsilanti, Athéna R; Rubenstein, John L R (2016) Transcriptional and epigenetic mechanisms of early cortical development: An examination of how Pax6 coordinates cortical development. J Comp Neurol 524:609-29
Gobius, Ilan; Morcom, Laura; Suárez, Rodrigo et al. (2016) Astroglial-Mediated Remodeling of the Interhemispheric Midline Is Required for the Formation of the Corpus Callosum. Cell Rep 17:735-747
Notwell, James H; Heavner, Whitney E; Darbandi, Siavash Fazel et al. (2016) TBR1 regulates autism risk genes in the developing neocortex. Genome Res 26:1013-22
Nord, Alex S; Pattabiraman, Kartik; Visel, Axel et al. (2015) Genomic perspectives of transcriptional regulation in forebrain development. Neuron 85:27-47
Prochazka, Jan; Prochazkova, Michaela; Du, Wen et al. (2015) Migration of Founder Epithelial Cells Drives Proper Molar Tooth Positioning and Morphogenesis. Dev Cell 35:713-24
Hoch, Renée V; Lindtner, Susan; Price, James D et al. (2015) OTX2 Transcription Factor Controls Regional Patterning within the Medial Ganglionic Eminence and Regional Identity of the Septum. Cell Rep 12:482-94
Hoch, Renée V; Clarke, Jeffrey A; Rubenstein, John L R (2015) Fgf signaling controls the telencephalic distribution of Fgf-expressing progenitors generated in the rostral patterning center. Neural Dev 10:8

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