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.
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.
|Chen, Yi-Hsien; Cimino, Patrick J; Luo, Jingqin et al. (2016) ABCG1 maintains high-grade glioma survival in vitro and in vivo. Oncotarget 7:23416-24|
|Bender, R Hugh F; Haigis, Kevin M; Gutmann, David H (2015) Activated k-ras, but not h-ras or N-ras, regulates brain neural stem cell proliferation in a raf/rb-dependent manner. Stem Cells 33:1998-2010|
|Chen, Yi-Hsien; McGowan, Lucy D'Agostino; Cimino, Patrick J et al. (2015) Mouse low-grade gliomas contain cancer stem cells with unique molecular and functional properties. Cell Rep 10:1899-912|
|Chen, Yi-Hsien; Gianino, Scott M; Gutmann, David H (2015) Neurofibromatosis-1 regulation of neural stem cell proliferation and multilineage differentiation operates through distinct RAS effector pathways. Genes Dev 29:1677-82|
|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|
|Gutmann, David H; Parada, Luis F; Silva, Alcino J et al. (2012) Neurofibromatosis type 1: modeling CNS dysfunction. J Neurosci 32:14087-93|
|Lee, Da Yong; Gianino, Scott M; Gutmann, David H (2012) Innate neural stem cell heterogeneity determines the patterning of glioma formation in children. Cancer Cell 22:131-8|
|Kaul, Aparna; Chen, Yi-Hsien; Emnett, Ryan J et al. (2012) Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner. Genes Dev 26:2561-6|
|Weber, Jason D; Gutmann, David H (2012) Deconvoluting mTOR biology. Cell Cycle 11:236-48|
Showing the most recent 10 out of 12 publications