I hypothesize that Fgf signaling from the rostral patterning center plays a major role in governing growth and patterning of the rostral telencephalon, including the frontal cortex. The experiments described below are designed to identify the molecular mechanisms that control: 1) Fgf expression and signaling;2) how Fgfs, and other signals, regulate expression of enhancers that drive expression in the developing frontal cortex;3) morphogenesis of the rostral telencephalon (frontal cortex and septum). The proposal has four Aims:
Aim I. Characterize the fates of cells in the rostral patterning center.
Aim II. Identify mechanisms that regulate gene expression in the rostral patterning center.
Aim III. Investigate the regulation of frontal cortex patterning: identify and characterize enhancers that define subdivisions of the frontal cortex.
Aim I V. Analyze roles of Fgf signal regulation in the rostral patterning center: analysis of Sprouty1, 2 and 1/2 mutants. I believe that these experiments will provide a firm foundation for elucidating the genetic, molecular, and cellular mechanisms that control development of the cerebral cortex and that may underlie some Human neurodevelopmental disorders such as Autism, Schizophrenia, and Epilepsy.

Public Health Relevance

Disruption of cerebral cortex development and function is strongly associated with several major neuropsychiatric disorders, including autism and schizophrenia. The experiments proposed in this application aim to elucidate basic mechanisms that underlie normal development of prefrontal cortex, an integral region subserving higher cognitive function. This information will provide a key foundation for understanding the genetic and molecular mechanisms underlying many psychiatric disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Riddle, Robert D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Eckler, Matthew J; Larkin, Kathryn A; McKenna, William L et al. (2014) Multiple conserved regulatory domains promote Fezf2 expression in the developing cerebral cortex. Neural Dev 9:6
Thompson, Carol L; Ng, Lydia; Menon, Vilas et al. (2014) A high-resolution spatiotemporal atlas of gene expression of the developing mouse brain. Neuron 83:309-23
Pattabiraman, Kartik; Golonzhka, Olga; Lindtner, Susan et al. (2014) Transcriptional regulation of enhancers active in protodomains of the developing cerebral cortex. Neuron 82:989-1003
Miraoui, Hichem; Dwyer, Andrew A; Sykiotis, Gerasimos P et al. (2013) Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet 92:725-43
Visel, Axel; Taher, Leila; Girgis, Hani et al. (2013) A high-resolution enhancer atlas of the developing telencephalon. Cell 152:895-908
McKenna, William L; Betancourt, Jennifer; Larkin, Kathryn A et al. (2011) Tbr1 and Fezf2 regulate alternate corticofugal neuronal identities during neocortical development. J Neurosci 31:549-64
Rubenstein, John L R (2011) Annual Research Review: Development of the cerebral cortex: implications for neurodevelopmental disorders. J Child Psychol Psychiatry 52:339-55
Faedo, Andrea; Borello, Ugo; Rubenstein, John L R (2010) Repression of Fgf signaling by sprouty1-2 regulates cortical patterning in two distinct regions and times. J Neurosci 30:4015-23
Moldrich, Randal X; Pannek, Kerstin; Hoch, Renee et al. (2010) Comparative mouse brain tractography of diffusion magnetic resonance imaging. Neuroimage 51:1027-36
Hoch, Renee V; Rubenstein, John L R; Pleasure, Sam (2009) Genes and signaling events that establish regional patterning of the mammalian forebrain. Semin Cell Dev Biol 20:378-86

Showing the most recent 10 out of 38 publications