A diverse group of adult and pediatric CNS disorders, such as multiple sclerosis and periventricular leukomalacia, the leading cause of cerebral palsy, share a common feature of insult to myelin-producing oligodendrocytes. The long-term goal of my research is to understand the biology of oligodendrocyte production and maturation with a view towards how remyelination could be therapeutically enhanced in the setting of white matter pathology. The proposed research focuses on the molecular mechanisms regulating these processes within the postnatal rodent brain. The adult subventricular zone (SVZ) recently has been identified as a site of ongoing oligodendrogenesis. To characterize the progenitor populations and genetic factors involved in postnatal oligodendrogenesis, I will study the molecular expression profile of cells in the adult SVZ using a combination of immunohistochemical techniques and confocal microscopy. I will determine changes in proliferation and expression of SVZ progenitors in response to focal demyelinating lesion in the corpus callosum, and correlate these with changes in oligodendrocyte production, recruitment to the site of injury, and remyelination. My prior work indicates that Dlx homeobox transcription factors act as repressors of oligodendrocyte formation and maturation during embryogenesis. In the proposed project, I will examine the role of Dlx in postnatal oligodendrogenesis by generating conditional Dlx2 knockout mice with loss of Dlx2 function in postnatal SVZ progenitors, as well as ectopically expressing Dlx2 using viral transduction. Cell transplantation of oligodendrocyte precursors (OPCs) has been suggested as a potential repair strategy in both acquired and congenital disorders of myelination. Since OPCs from Dlx1&2 null mice show accelerated maturation, I will investigate whether heterochronic grafting of these cells (versus wild type OPCs) in a mouse model of congenital leukodystrophy leads to more robust myelination and improved survival. In summary, this project will be the first detailed analysis of Dlx function in postnatal oligodendrogenesis and in endogenous responses to demyelinating injury, and offer insight into whether manipulation of Dlx in genetically engineered cells could enhance their myelinating potential. Lay Summary: Common pediatric and adult neurological disorders, such as cerebral palsy and multiple sclerosis, are characterized by damage to the brain's white matter due to loss or dysfunction of myelin producing oligodendrocytes. This research project investigates stem cells within the adult rodent brain that could serve as endogenous sources of oligodendrocytes, the response of these cells in animal models of white matter injury, and the effectiveness of cell-transplantation paradigms to treat a congenital disorder of myelin formation or leukodystrophy.
|Potter, Gregory B; Rowitch, David H; Petryniak, Magdalena A (2011) Myelin restoration: progress and prospects for human cell replacement therapies. Arch Immunol Ther Exp (Warsz) 59:179-93|
|Sun, Yu; Meijer, Dimphna H; Alberta, John A et al. (2011) Phosphorylation state of Olig2 regulates proliferation of neural progenitors. Neuron 69:906-17|