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Developmental regulation of gliogenesis in the mammalian CNS is incompletely understood, in part due to a limited repertoire of lineage-specific genes. We used Aldh1l1-GFP as a marker for gliogenic radial glia and later-stage precursors of developing astrocytes and performed gene expression profiling of these cells. We then used this dataset to identify candidate transcription factors that may serve as glial markers or regulators of glial fate. Our analysis generated a database of developmental stage-related markers of Aldh1l1+ cells between murine embryonic day 13.5-18.5. Using these data we identify the bZIP transcription factor Nfe2l1 and demonstrate that it promotes glial fate under direct Sox9 regulatory control. Thus, this dataset represents a resource for identifying novel regulators of glial development., (Copyright © 2013 Wiley Periodicals, Inc.)

Objective: Chronic demyelination can result in axonopathy and is associated with human neurological conditions such as multiple sclerosis (MS) in adults and cerebral palsy in infants. In these disorders, myelin regeneration is inhibited by impaired differentiation of oligodendrocyte progenitors into myelin-producing oligodendrocytes. However, regulatory factors relevant in human myelin disorders and in myelin regeneration remain poorly understood. Here we have investigated the role of the transcription factor nuclear factor IA (NFIA) in oligodendrocyte progenitor differentiation during developmental and regenerative myelination., Methods: NFIA expression patterns in human neonatal hypoxic-ischemic encephalopathy (HIE) and MS as well as developmental expression in mice were evaluated. Functional studies during remyelination were performed using a lysolecithin model, coupled with lentiviral misexpression of NFIA. The role of NFIA during oligodendrocyte lineage development was characterized using chick and mouse models and in vitro culture of oligodendrocyte progenitors. Biochemical mechanism of NFIA function was evaluated using chromatin immunoprecipitation and reporter assays., Results: NFIA is expressed in oligodendrocyte progenitors, but not differentiated oligodendrocytes during mouse embryonic development. Examination of NFIA expression in white matter lesions of human newborns with neonatal HIE, as well active MS lesions in adults, revealed that it is similarly expressed in oligodendrocyte progenitors and not oligodendrocytes. Functional studies indicate that NFIA is sufficient to suppress oligodendrocyte progenitor differentiation during adult remyelination and embryonic development through direct repression of myelin gene expression., Interpretation: These studies suggest that NFIA participates in the control of oligodendrocyte progenitor differentiation and may contribute to the inhibition of remyelination in human myelin disorders., (Copyright © 2012 American Neurological Association.)

The progressive loss of CNS myelin in patients with multiple sclerosis (MS) has been proposed to result from the combined effects of damage to oligodendrocytes and failure of remyelination. A common feature of demyelinated lesions is the presence of oligodendrocyte precursors (OLPs) blocked at a premyelinating stage. However, the mechanistic basis for inhibition of myelin repair is incompletely understood. To identify novel regulators of OLP differentiation, potentially dysregulated during repair, we performed a genome-wide screen of 1040 transcription factor-encoding genes expressed in remyelinating rodent lesions. We report that approximately 50 transcription factor-encoding genes show dynamic expression during repair and that expression of the Wnt pathway mediator Tcf4 (aka Tcf7l2) within OLPs is specific to lesioned-but not normal-adult white matter. We report that beta-catenin signaling is active during oligodendrocyte development and remyelination in vivo. Moreover, we observed similar regulation of Tcf4 in the developing human CNS and lesions of MS. Data mining revealed elevated levels of Wnt pathway mRNA transcripts and proteins within MS lesions, indicating activation of the pathway in this pathological context. We show that dysregulation of Wnt-beta-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of beta-catenin in the oligodendrocyte lineage in vivo and (2) findings from APC(Min) mice, which lack one functional copy of the endogenous Wnt pathway inhibitor APC. Together, our findings indicate that dysregulated Wnt-beta-catenin signaling inhibits myelination/remyelination in the mammalian CNS. Evidence of Wnt pathway activity in human MS lesions suggests that its dysregulation might contribute to inefficient myelin repair in human neurological disorders.

Olig1 and Olig2 encode basic helix-loop-helix (bHLH) transcription factors that are expressed in both the developing and mature vertebrate central nervous system. While numerous studies have established critical functions for Olig genes during the formation of motor neurons and oligodendrocytes of the ventral neural tube, their roles at later stages of development and in adulthood have remained relatively obscure. Recent studies, however, reveal that in the fetal dorsal spinal cord and neural progenitor cells of the adult brain, Olig expression continues to mark, and may regulate, the formation of oligodendroglia. Studies of Olig expression in human brain tumors and repair of demyelinating lesions suggest the possibility of additional functions in a variety of neurological diseases., (Copyright 2005 Wiley-Liss, Inc.)