Structural hippocampal and neocortical abnormalities underlie many cases of epilepsy and these structures are required for learning and memory. More subtle defects of hippocampal development are also associated with mental retardation, autism spectrum disorders and schizophrenia and most recently in affective disorders. To understand these disorders it is necessary to improve our basic understanding of the regulation of cortical development. Recent studies show that members of the Wnt family of secreted factors are important in the development of the hippocampus. The hippocampus forms from the neuroepithelium adjacent to a midline organizing structure called the cortical hem. The cortical hem secretes many putative morphogenic factors including a variety of Wnts. Wnt signaling has been demonstrated to regulate hippocampal development, as several lines of mutant mice with defects in Wnt signaling have severe defects in hippocampal development. My primary hypothesis is that Wnt signaling components, including Wnt receptors and effectors control the morphogenesis of the dentate gyrus by controlling proliferation and cell fate of granule cell neurons. My secondary hypothesis is that these signaling components also regulate a variety of developmental processes in other regions of the hippocampus and neocortex. These hypotheses will be addressed by 3 specific aims - 1) Regulation of dentate granule cell production by Wnt/B-catenin signaling; 2) Wnt signaling functions in neocortical development; 3) Determine the functions of Frizzled9 and 10 in the developing cortex. This proposal represents a continuation of Career Development as an independent scientist. Salary support for these activities is sought in conjunction with an already funded award for these studies but this salary support will cover a large portion of the applicant's salary providing the freedom to pursue the scientific goals of the proposal without excess clinical burden. A detailed career development plan is included as a part of the proposal, as is departmental assurance of support in these activities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research (K02)
Project #
1K02MH074958-01
Application #
6958670
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Sieber, Beth-Anne
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$113,724
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Pino, Darya; Choe, Youngshik; Pleasure, Samuel J (2011) Wnt5a controls neurite development in olfactory bulb interneurons. ASN Neuro 3:e00059
Munji, Roeben N; Choe, Youngshik; Li, Guangnan et al. (2011) Wnt signaling regulates neuronal differentiation of cortical intermediate progenitors. J Neurosci 31:1676-87
Li, Guangnan; Pleasure, Samuel J (2010) Ongoing interplay between the neural network and neurogenesis in the adult hippocampus. Curr Opin Neurobiol 20:126-33
Pozniak, Christine D; Langseth, Abraham J; Dijkgraaf, Gerrit J P et al. (2010) Sox10 directs neural stem cells toward the oligodendrocyte lineage by decreasing Suppressor of Fused expression. Proc Natl Acad Sci U S A 107:21795-800
Freese, Jennifer L; Pino, Darya; Pleasure, Samuel J (2010) Wnt signaling in development and disease. Neurobiol Dis 38:148-53
Langseth, Abraham J; Munji, Roeben N; Choe, Youngshik et al. (2010) Wnts influence the timing and efficiency of oligodendrocyte precursor cell generation in the telencephalon. J Neurosci 30:13367-72
Gu, Xiaochun; Yan, Yan; Li, Hanlin et al. (2009) Characterization of the Frizzled10-CreER transgenic mouse: an inducible Cre line for the study of Cajal-Retzius cell development. Genesis 47:210-6
Siegenthaler, Julie A; Ashique, Amir M; Zarbalis, Konstantinos et al. (2009) Retinoic acid from the meninges regulates cortical neuron generation. Cell 139:597-609
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
Sall, Jeffrey W; Stratmann, Greg; Leong, Jason et al. (2009) Isoflurane inhibits growth but does not cause cell death in hippocampal neural precursor cells grown in culture. Anesthesiology 110:826-33

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