Adult mammalian neural stem cells are a subject of intense study based on their biological properties and potential medical significance. Neural stem cells can self-renew and differentiate into neurons and glial cells (astrocytes and oligodendrocytes) during development and also in the adult central nervous system. We are interested in the identification of the cellular and molecular mechanisms regulating self-renewal and fate specification of adult neural stem cells and plasticity of newborn neurons in the dentate gyrus of the hippocampus. Our laboratory is using an integrated approach to investigate rodent and human neural stem cells both in vitro and in animal models utilizing techniques in molecular biology, cell biology, virology, and imaging.
Epigenetic control of adult neural stem cell fate:
Neural development and plasticity is determined by both extrinsic and intrinsic factors. These two interface at the regulation of gene programs that control neuronal cell fate and function. Using an in vitro culture system, we previously demonstrated that chromatin remodeling and histone modifications play an important role in neuronal cell fate specification. We are currently examining the underlying mechanisms using molecular and biochemical approaches.
Signal transduction mechanisms for neurogenesis and gliogenesis:
One model for the regulation of neural progenitor cell fate is that multiple signaling pathways are activated by epigenetic mechanisms. Thus, in addition to studying events in the nucleus that control neural progenitor fate determination, we are interested in the cytoplasmic signaling pathways that regulate the potential of neural stem cells. Previously, we discovered that adult neural progenitor oligodendrocyte differentiation requires both the removal of FGF-2 and the addition of IGF-I suggesting an important role for FGF and IGF signaling pathways. Current work is focused on downstream signaling mediators of receptor protein tyrosine kinases in the control of neurogenesis and gliogenesis.
Animal models for the study of neural stem cell fate decisions:
Differentiation of adult neural stem cells in vitro is a powerful method for studying single factors in fate specification, however one of the key questions is to understand the control of how neural stem cells choose their fates in vivo. In collaboration with Dr. Eric Olson, we are investigating the role of chromatin remodeling in adult neural stem cell biology using knock-out mouse models.
Stem cells in the adult brain present a particularly intriguing area of study. Although we have seen a good deal of progress in our understanding of the specific requirements of neural stem cells to proliferate and differentiate along specific lineages, the next step is to determine the mechanistic connections between local environmental signals and their immediate targets that regulate stem cell fate. Answers to these questions will advance our understanding of basic developmental processes, and may shed light for therapeutic intervention in degenerative neurological diseases, such as Parkinsons, Epilepsy, and Multiple Sclerosis.
RESEARCH INTERESTS
Stem Cell Biology
Neurogenesis and Gliogenesis in CNS
Chromatin Remodeling
Neurological Diseases
RECENT PUBLICATIONS
Hsieh, J., Nakashima K., Kuwabara T., Mejia E., and Gage F.H., "Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells" Proc Natl Acad Sci USA, 101:16659-16664, November 2004
Kuwabara T., Hsieh J., Nakashima K., Taira K., and Gage F.H., "A small modulatory dsRNA specifies the fate of adult neural stem cells" Cell, 116:779-793, March 2004
Hsieh J., Aimone J.B., Kaspar B.K., Kuwabara T., Nakashima K., and Gage F.H., "IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes" Journal of Cell Biology, 164:111-122, January 2004
Hsieh, J. and Gage F.H., "Epigenetic control of neural stem cell fate" Current Opinion in Genetics and Development, 14:461-469, Spring 2004
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