UCSF

Oligodendrocytes are the myelinating cells of the central nervous system (CNS). By enabling rapid nerve conduction and in turn the dense packing of relatively small-bore axons into white matter tracts, myelination was essential for the evolution of the complex vertebrate brain. Permanent dysmyelination of the CNS is a central component of injuries that cause cerebral palsy and cognitive disabilities, as well as Multiple Sclerosis. The factors that instruct oligodendrocyte specification, proliferation, maturation and their ultimate matching to axonal partners is thus an essential question of both basic and clinical neuroscience.

My dissertation focuses on two distinct transcriptional mechanisms that respectively regulate: (1) the initial allocation oligodendrocytes from multipotent progenitors and (2) the onset of oligodendrocyte maturation and myelination. I first demonstrate that the bHLH transcription factor Olig1 is expressed in radial glia of the ventral telencephalon. Olig1 promotes production of oligodendrocytes and represses production of GABAergic interneurons throughout the mouse brain. Olig1 deletion in mutant mice results in ectopic expression and upregulation of Dlx1/2 genes in the ventral medial ganglionic eminences and adjacent regions of the septum resulting in a ~30% increase in adult cortical interneuron numbers with corresponding diminution of oligodendrocyte lineage cells in the embryo and adult. I show that Olig1 directly represses the Dlx1/2 I12b intergenic enhancer and that Dlx1/2 functions genetically downstream of Olig1. I find that Olig1 is likewise responsible for neuron versus oligodendrocyte specification during repair phases of forebrain Hypoxic-ischemic encephalopathy. These findings build on previous studies that suggest there is common origin of oligodendrocytes and interneurons in the telencephalon. They further establish Olig1 as an essential repressor of Dlx1/2 and interneuron production in developing mammalian brain.

In a second set of studies, I have investigated roles for Hypoxia Inducible Factors (HIFs) in regulating oligodendrocyte ontogeny. Though, HIFs are largely dispensable for oligodendrocyte specification, they are essential regulators of postnatal oligodendrocyte maturation. This work has also elucidated a surprising cell intrinsic role for oligodendrocytes in the coordination of myelination and white matter angiogenesis. Here I show that O2 tension, mediated by OPC-encoded Hypoxia-inducible factor (HIF) function, is an essential regulator of postnatal myelination. Constitutive HIF1/2α stabilization resulted in OPC maturation arrest through autocrine activation of canonical Wnt7a/7b. Surprisingly, such OPCs also show paracrine activity that induces excessive postnatal white matter angiogenesis in vivo, and directly stimulates endothelial cell proliferation in vitro. Conversely, OPC-specific HIF1/2α loss-of-function leads to insufficient angiogenesis in corpus callosum and catastrophic axon loss. These findings establish that OPC-intrinsic HIF signaling is essential for postnatal white matter angiogenesis and for synchronizing vascularization with the onset of myelination in the mammalian brain. Taken together these studies reveal novel transcriptional mechanisms involved in broad aspects of oligodendrocyte ontogeny, which play overlapping roles in the pathophysiology of developmental white matter injury.