Normal mammalian brain development involves the regulated growth of progenitor cells and their differentiation into specialized cell types. Abnormalities in progenitor cell function during embryogenesis can lead to inappropriate expansion of stem cell populations and abnormal glial maturation, and potentially result in a number of brain abnormalities, including the formation of brain tumors in children. Neurofibromatosis type 1 (NF1) is one of the most common genetic conditions in which affected children develop glial cell tumors (optic pathway gliomas). Using NF1 as a model system to study neural stem/progenitor cell (NSC) function in vitro and in vivo, we have shown that loss of Nf1 protein (neurofibromin) function in embryonic NSCs results in (1) increased NSC proliferation and self-renewal and (2) increased glial lineage expansion. Based on our experimental observations, we hypothesize that neurofibromin is required for NSC maintenance and glial cell maturation in vivo. In this proposal, we have designed complementary in vitro and in vivo experiments to determine how neurofibromin controls NSC maintenance and glial cell differentiation. The overall objective of this proposal is to employ laboratory-generated genetically-engineered Nf1 mutant mice and Nf1-deficient NSCs as tractable experimental platforms to define the critical control mechanisms that govern NSC function in the developing central nervous system.

Public Health Relevance

The most common genetic condition in which children develop brain tumors is neurofibromatosis type 1 (NF1). This proposal employs NF1 as an experimental model system to understand the role of neural stem cells in normal brain development in mice relevant to brain tumor formation. These studies may lead to the development of therapies that specifically target the critical growth and fate control pathways that cause brain tumors in children.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Fisher, Michael J; Avery, Robert A; Allen, Jeffrey C et al. (2013) Functional outcome measures for NF1-associated optic pathway glioma clinical trials. Neurology 81:S15-24
Kaul, Aparna; Chen, Yi-Hsien; Emnett, Ryan J et al. (2013) Conditional KIAA1549:BRAF mice reveal brain region- and cell type-specific effects. Genesis 51:708-16
Weber, Jason D; Gutmann, David H (2012) Deconvoluting mTOR biology. Cell Cycle 11:236-48
Dahiya, Sonika; Lee, Da Yong; Gutmann, David H (2011) Comparative characterization of the human and mouse third ventricle germinal zones. J Neuropathol Exp Neurol 70:622-33
Lee, Da Yong; Yeh, Tu-Hsueh; Emnett, Ryan J et al. (2010) Neurofibromatosis-1 regulates neuroglial progenitor proliferation and glial differentiation in a brain region-specific manner. Genes Dev 24:2317-29