Abnormalities of glia contribute to a wide range of neurologic diseases. However, many important aspects of glial biology and development remain poorly understood. The basic helix-loop-helix transcription factor, Olig2, is essential for motor neuron and oligodendrocyte development in the mouse spinal cord. Yet, fundamental aspects of its function have not been elucidated. The in vivo potential of individual Olig2+ progenitor cells within the microenvironment of the neural tube is unknown; and potential functions for Olig2 during forebrain development and glial tumor formation are untested. The key hypothesis of this grant application is that Olig2+ progenitors give rise to neurons and oligodendrocytes - but not astrocytes - in the developing CNS and are a key cell type in glioma formation. The following studies are proposed to test this hypothesis:
Specific Aim 1 : Generate a multifunctional transgenic mouse """"""""knock-in"""""""" of the tva avian retroviral receptor and cre recombinase into the Olig2 locus (Olig2-tva-cre). This mouse will be used for fate mapping and other studies in the proposal.
Specific Aim 2 : Determine whether individual Olig2+ progenitors in the ventral neural tube are bipotent and give rise, first to neurons, and then to oligodendrocytes. This will be tested by clonally infecting Olig2-tva-cre derived neural tube, explants, and neural stem cells with RCAS reporter viruses to trace the fate of labeled progeny. The major innovation of this approach is that reporter virus will be targeted solely to Olig2-tva+ progenitors.
Specific Aim 3 : Determine whether Olig2 function is required for development of telencephalic neuronal subtypes. The hypothesis that Olig2 function is required for forebrain neuronogenesis will be tested by comparative immunohistologic analysis and deconvolution microscopy of Olig2 null and heterozygous littermates.
Specific Aim 4 : Determine the contributions of Olig2+ progenitors to mouse models of glial tumors and the functional requirements for Olig2 in gliomagenesis. Overall, this proposal should provide insight into regulation of glial development and glial tumors. Such understanding is essential for targeted molecular approaches to the diagnosis and treatment of neurologic diseases such as multiple sclerosis, neurodegeneration, and brain tumors. In addition, this proposal outlines an integrated research training plan and detailed career development plan which should facilitate the transition to full academic independence in the neuroscience community of Harvard Medical School. ? ?
|Holmberg Olausson, Karl; Maire, Cecile L; Haidar, Sam et al. (2014) Prominin-1 (CD133) defines both stem and non-stem cell populations in CNS development and gliomas. PLoS One 9:e106694|
|Maire, Cécile L; Ramkissoon, Shakti; Hayashi, Marika et al. (2014) Pten loss in Olig2 expressing neural progenitor cells and oligodendrocytes leads to interneuron dysplasia and leukodystrophy. Stem Cells 32:313-26|
|Poduri, Annapurna; Evrony, Gilad D; Cai, Xuyu et al. (2012) Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 74:41-8|
|Mehta, Shwetal; Huillard, Emmanuelle; Kesari, Santosh et al. (2011) The central nervous system-restricted transcription factor Olig2 opposes p53 responses to genotoxic damage in neural progenitors and malignant glioma. Cancer Cell 19:359-71|
|Santagata, Sandro; Maire, Cecile L; Idbaih, Ahmed et al. (2009) CRX is a diagnostic marker of retinal and pineal lineage tumors. PLoS One 4:e7932|
|Schuller, Ulrich; Heine, Vivi M; Mao, Junhao et al. (2008) Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 14:123-34|
|Ligon, Keith L; Huillard, Emmanuelle; Mehta, Shwetal et al. (2007) Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma. Neuron 53:503-17|
|Ligon, Keith L; Kesari, Santosh; Kitada, Masaaki et al. (2006) Development of NG2 neural progenitor cells requires Olig gene function. Proc Natl Acad Sci U S A 103:7853-8|
|Santagata, Sandro; Hornick, Jason L; Ligon, Keith L (2006) Comparative analysis of germ cell transcription factors in CNS germinoma reveals diagnostic utility of NANOG. Am J Surg Pathol 30:1613-8|