David H. Gutmann, M.D., Ph.D.
Donald O. Schnuck Family Professor
Vice Chair for Research Affairs
Molecular Genetics and Genomics Program
Molecular Cell Biology Program
2208 McMillan Building
brain cancer, brain development, neurons, neural stem cells, glia, genetically-engineered mouse models, learning and behavior, iPSCs, signal transduction, sexual dimorphism
Using mouse models to understand normal brain and brain tumor development
The development of the mammalian brain is a highly regulated process involving both cell-autonomous and non-cell-autonomous decisions that determine cell fate, proliferation, migration, and death. The genes that govern these critical decisions are often mutated in human neurogenetic conditions. One of the most common of these disorders is neurofibromatosis type 1 (NF1).
Using NF1 as a model genetic system to understand normal growth and differentiation in the normal brain, our laboratory aims to characterize the genetic, cellular, and molecular factors that contribute to the development of nervous system tumors (gliomas and neurofibromas) and cognitive problems (learning and attention deficits). Defining these contributing factors represents the first step toward establishing new treatments for children and adults with NF1. Moreover, NF1 provides unique opportunities to unravel the complexities of related medical problems in the general population, including adult and childhood brain tumors, breast cancer, and autism.
We employ these single gene disorders as model genetic platforms to understand how genomic, tissue, cellular and molecular factors control normal neural stem cell, neuron and glial function in vitro and in vivo. To accomplish these goals, we have generated numerous genetically-engineered mouse models and human induced pluripotent stem cell lines.
Current research in our laboratory includes:
• The impact of Ras signaling, mammalian target of rapamycin (mTOR) activity, and intracellular cyclic AMP generation in specifying cell proliferation, cell death, and differentiation in the brain
• The instructive role of the tumor microenvironment, specifically microglia (macrophage-like cells), in dictating brain tumor formation and growth
• The diversity of neural stem cell function as defined by the brain region of origin
• The relationship between brain region-specific neural stem cells and cancer development in children and adults
• The molecular and genomic determinants that underlie cognitive and behavioral dysfunction in neurons
Dr. Gutmann`s work was profiled by the journal Nature Neuology in August 2014 (http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(14)70163-2/fulltext).
Smithson LJ, Gutmann DH. Proteomic analysis reveals GIT1 as a novel mTOR complex component critical for mediating astrocyte survival. Genes Dev 30:1383-1388, 2016. PMID: 27340174
Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia/macrophages in glioma maintenance and progression. Nat Neurosci 19:20-27, 2015. PMID: 26713745
Chen YH, Gianino SM, Gutmann DH: Neurofibromatosis-1 regulation of neural stem cell proliferation and multi-lineage differentiation operates through distinct RAS effector pathways. Genes and Development 29:1677-1682, 2015. PMID: 26272820
Chen Y-H, D’Agostino McGowan L, Cimino PJ, Dahiya S, Leonard JR, Lee DY, Gutmann DH: Mouse low-grade gliomas contain cancer stem cells with unique molecular and functional properties. Cell Reports 10:1899-1912, 2015. PMID: 25772366
Anastasaki C, Woo AS, Messiaen LM, Gutmann DH: Elucidating the impact of neurofibromatosis-1 germline mutations on neurofibromin function and dopamine-based learning. Hum Mol Genet 24:3518-28, 2015. PMID: 25772366
Lee DY, Gianino SM, Gutmann DH: Innate neural stem cell heterogeneity determines the patterning of glioma formation in children. Cancer Cell 22:131-8, 2012. PMID: 22789544
Kaul A, Chen Y-H, Emnett RJ, Dahiya S, Gutmann DH: Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner. Genes & Development 26:2561-6, 2012. PMID: 23152448
Banerjee S, Crouse NR, Emnett RJ, Gianino SM, Gutmann DH: Neurofibromatosis-1 regulates mTOR-mediated astrocyte growth and glioma formation in a TSC/Rheb-independent manner. Proc Natl Acad Sci USA 108:15996-6001, 2011. PMID: 21896734
Lee DY, Yeh T-H, Emnett RJ, White CR, Gutmann DH: Neurofibromatosis-1 regulates neuroglial progenitor proliferation and glial differentiation in a brain region-specific manner. Genes & Development 24:2317-29, 2010. PMID: 20876733
Hegedus B, Dasgupta B, Shin JE, Emnett RJ, Hart-Mahon EK, Elghazi L, Bernal-Mizrachi E, Gutmann DH: Neurofibromatosis-1 regulates neuronal and glial cell differentiation from neuroglial progenitors in vivo by both cAMP- and Ras-dependent mechanisms. Cell Stem Cell 1:443-457, 2007. PMID: 18371380
Last Updated: 11/1/2016 11:55:21 AM
Abnormal differentiation of neural stem cells