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Overlapping Mechanisms in CNS Development and Neurological Disease
Summary: David Rowitch is working to understand how problems that arise during development, particularly among the glial cells that support neurons in the brain, can lead to cerebral palsy.
My laboratory focuses on common mechanisms in vertebrate central nervous system (CNS) development that have additional roles in human neurological diseases. Repair mechanisms in the brain may recapitulate a developmental sequence or, alternatively, become dysregulated, leading to neurological disease or cancer. At UCSF, my laboratory is part of the newly founded Newborn Brain Research Institute, which brings together neuroscientists, pathologists, and clinicians to generate novel approaches to characterize, diagnose, and treat newborn neurological injuries.
Sonic hedgehog (Shh) is a secreted protein that is necessary for pattern formation in the embryonic CNS. Shh also causes proliferation of certain types of immature CNS cells, including cerebellar granule neuron precursors (CGNPs). Abnormal activation of Shh signaling in CGNPs is etiologic in the most common type of pediatric brain tumor, medulloblastoma. We have studied developing CGNP to learn more about medulloblastoma progenitors, tumor initiation, and growth. My laboratory participates in the UCSF Pediatric Brain Tumor Research Center, which seeks to define the cellular origins, molecular events, and signaling pathways that lead to medulloblastoma and pediatric gliomas, and to generate tumor models for preclinical testing. Most recently, our group has identified activating mutations of the Ras pathway protein BRAF as a common oncogenic mutation causing pediatric glioma.
Glia comprise the white matter of the brain and collectively are the most numerous cells in the brain, yet many aspects of their development and function remain poorly understood. In collaboration with Charles Stiles (Harvard Medical School), we identified and characterized the Shh-regulated Olig1 and Olig2 genes. (Olig genes were independently identified and characterized by David Anderson [HHMI, California Institute of Technology] and Thomas Jessell [HHMI, Columbia University]). Our work has shown that Olig function is essential for development of myelinating oligodendrocytes and motor neurons throughout the CNS. This dual requirement for Olig function in a neuron and glial lineage was the first genetic data to argue against the traditional view that oligodendrocytes and astrocytes develop in tandem via a glial-restricted precursor cell. A major effort of our laboratory is to understand astrocyte functional and molecular heterogeneity and the developmental programs that direct astrogenesis in various domains of the CNS. We are therefore seeking to define transcription factors, such as the basic helix-loop-helix (bHLH) protein SCL (stem cell leukemia), that regulate astrocyte development in regionally restricted domains of the CNS.
We are also analyzing Olig functions in neural stem cells and in human brain cancer, multiple sclerosis, and periventricular leukomalacia (PVL), a serious neurological complication of premature delivery in which white matter tracts are damaged, leading to cognitive and motor deficits. Premature infant brain injury is the leading cause contributing to the increased incidence of cerebral palsy in the United States. We recently founded a novel brain bank that collects tissue samples for pediatric neurological diseases, which provides critical material for in-depth analysis of pathobiological mechanisms.
Finally, I also direct clinical projects aimed at testing new biological approaches for white matter disease and new approaches for the care of newborns at risk for neurological injury. One of these is a phase I clinical study to test the safety of implanting human neural stem cells to treat a rare congenital disorder called Pelizaeus-Merzbacher disease (PMD), in which oligodendrocytes are defective. In addition, in 2008, we formed the UCSF Neuro-Intensive Care Nursery, a multidisciplinary clinical unit that brings together neonatologists, neurologists, and specialized nursing and other personnel to optimize care for infants at risk of neurological injury. The Neuro-Intensive Care Nursery also provides a research platform for new neuroprotective clinical studies in these vulnerable patients.
As of January 21, 2011
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