During embryonic and post-natal development, the neurons and macroglia of the mammalian central nervous system originate from a homogeneous population of multipotential neural stem cells. Extracellular growth factor stimulation is one mechanism by which these stem cells can be induced to undergo progressive lineage restriction and differentiation in vitro. Examples of this include the differentiation of stem cells into neurons and astrocytes by platelet-derived growth factor (PDGF) and ciliary neurotrophic factor (CNTF), respectively. These and other soluble growth factors bind to their cognate receptors, activate a panoply of intertwined signal transduction networks, and lead to the transcription of phenotype determining and restricting genes. The focus of this project is to better understand the mechanisms by which stem cells integrate the multiple, and at times opposing, growth factor induced signals, and select an ultimate lineage phenotype. Specifically, we are studying the roles of various transcriptional regulatory mechanisms in determining the expression patterns of selected astrocyte- and neuron- specific genes. The overall goal of our work is to better understand the process of normal brain development. The insights gained will be used in the diagnosis and treatment of various clinical disorders such as brain tumors, neurodegenerative diseases, neuroinflammatory diseases, strokes and brain and spinal cord injuries.
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