My laboratory focuses on common signal transduction pathways required during development of the vertebrate brain that have additional roles in human neurological diseases. Sonic hedgehog (Shh) is a secreted protein that is critical for pattern formation in the embryonic central nervous system (CNS). Shh also causes proliferation of cerebellar granule neuron precursor cells (CGNPs), and abnormal activation of Hedgehog signaling is etiologic in the most common type of pediatric brain tumor, medulloblastoma.
Our work has shown that Shh is a mitogen that causes G1 progression in CGNPs via activation and stabilization of N-myc, in concert with phosphoinositide-3-kinase (PI-3K) signaling. We have identified similarities between gene expression in developing CGNP and human medulloblastoma to learn more about cancer progenitors and tumor clinical characteristics. My laboratory is an active participant 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.
In a second line of investigation, we are exploring the genetic factors required for development of glial subtypes. 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 College of Physicians and Surgeons]). Our work has shown that Olig function is essential for development of all oligodendrocytes throughout the brain and spinal cord in vertebrates. Olig gene function is also required for development of motor neurons of the spinal cord. This dual requirement for Olig function and other lines of evidence call into question the traditional view that oligodendrocytes develop via a glial-restricted precursor cell. We are 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, as a possible determinant of astrocyte functional and molecular heterogeneity.
We are also analyzing Olig gene regulation and functions in neural stem cells and in human neurological diseases such as 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. At UCSF, my laboratory is part of the newly founded Newborn Brain Research Institute, which will bring together neuroscientists, pathologists, and clinicians to generate novel approaches to characterize, diagnose, and treat newborn neurological injuries.
