Ascl1 controls the number and distribution of astrocytes and oligodendrocytes in the gray matter and white matter of the spinal cord

Vue, Tou Yia; Kim, Euiseok J.; Parras, Carlos; Guillemot, François; Johnson, Jane E.

doi:10.1242/dev.105270

Cited by 42 publications

(47 citation statements)

References 51 publications

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“…As previously reported (Parras et al, 2007; Sugimori et al, 2007; Sugimori et al, 2008; Vue et al, 2014), immunofluorescence for ASCL1 showed that it is highly expressed in glial progenitors and precursor cells that span the dorsal-ventral extent of the spinal cord at E14.5 (Fig. 1A).…”

Section: Resultssupporting

confidence: 86%

“…Statistical analyses were performed as previously described (Vue et al, 2014) to assess the differences in NG2-glia cell density or percentage expression of marker+;tdTOM+ cells in GM and WM between control and Ascl1 -CKO. In short, a linear regression technique to model the observed cell number as a linear combination of fixed effect (genotype) and random effect (animal ID) was used.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we and others reported that the bHLH transcription factor ASCL1, which is well known for its roles during neurogenesis, is broadly expressed in glial progenitor cells throughout the ventricular zone (VZ) at the onset of gliogenesis in the spinal cord and in the cortex (Nakatani et al, 2013; Parras et al, 2007; Sugimori et al, 2007; Sugimori et al, 2008; Vue, Kim, Parras, Guillemot, & Johnson, 2014). Notably, ASCL1 expression is maintained in NG2-glia as they migrate out of the ventricular zone to populate the surrounding GM and WM, but is downregulated once NG2-glia differentiate to become mature OLs (Nakatani et al, 2013; Vue et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Notably, ASCL1 expression is maintained in NG2-glia as they migrate out of the ventricular zone to populate the surrounding GM and WM, but is downregulated once NG2-glia differentiate to become mature OLs (Nakatani et al, 2013; Vue et al, 2014). Accordingly, Ascl1 mutant and conditional-knock out mice exhibit a significant decrease in the number of NG2-glia and OLs that are generated, particularly in the WM of the spinal cord (Battiste et al, 2007; Nakatani et al, 2013; Parras et al, 2007; Sugimori et al, 2007; Sugimori et al, 2008; Vue et al, 2014), suggesting that ASCL1 may play an important role in regulating the generation of NG2-glia in the CNS. However, the precise function of ASCL1 specifically in NG2-glia during embryonic development or in the adult CNS remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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ASCL1 regulates proliferation of NG2‐glia in the embryonic and adult spinal cord

Kelenis

Hart

Edwards-Fligner

et al. 2018

Glia

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NG2‐glia are highly proliferative oligodendrocyte precursor cells (OPCs) that are widely distributed throughout the central nervous system (CNS). During development, NG2‐glia predominantly differentiate into oligodendrocytes (OLs) to myelinate axon fibers, but they can also remain as OPCs persisting into the mature CNS. Interestingly, NG2‐glia in the gray matter (GM) are intrinsically different from those in the white matter (WM) in terms of proliferation, differentiation, gene expression, and electrophysiological properties. Here we investigate the role of the transcriptional regulator, ASCL1, in controlling NG2‐glia distribution and development in the GM and WM. In the spinal cord, ASCL1 levels are higher in WM NG2‐glia than those in the GM. This differential level of ASCL1 in WM and GM NG2‐glia is maintained into adult stages. Long‐term clonal lineage analysis reveals that the progeny of single ASCL1+ oligodendrocyte progenitors (OLPs) and NG2‐glia are primarily restricted to the GM or WM, even though they undergo extensive proliferation to give rise to large clusters of OLs in the postnatal spinal cord. Conditional deletion of Ascl1 specifically in NG2‐glia in the embryonic or adult spinal cord resulted in a significant reduction in the proliferation but not differentiation of these cells. These findings illustrate that ASCL1 is an intrinsic regulator of the proliferative property of NG2‐glia in the CNS.

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Section: Resultssupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

ASCL1 regulates proliferation of NG2‐glia in the embryonic and adult spinal cord

Kelenis

Hart

Edwards-Fligner

et al. 2018

Glia

Self Cite

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“…Higher KL levels in CC and lower levels in spinal cord imply that KL needs and functions may differ between these regions of the CNS and could explain the different effects of KL overexpression in the cuprizone and EAE models. For example, the conditional deletion of the transcription factor Ascl1 (Mash1) postneurogenesis shows that Ascl1 is required during oligodendrogenesis for generating the correct numbers of white matter, but not gray matter OPCs, suggesting that these cells are not created equally (Vue et al 2014). Also, mTOR was shown to be necessary for proper OL differentiation and myelination in the spinal cord, but not in the cortex.…”

Section: Discussionmentioning

confidence: 99%

The Anti-Aging Protein Klotho Enhances Remyelination Following Cuprizone-Induced Demyelination

Zeldich

Chen

Avila³

et al. 2015

J Mol Neurosci

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The current study examined whether overexpression of Klotho (KL) in transgenic mice can enhance remyelination following cuprizone-induced demyelination and improves the clinical outcome in experimental autoimmune encephalomyelitis (EAE). Demyelination was achieved by feeding transgenic mice overexpressing the transmembrane form of Klotho (KL-OE) and wild-type (WT) littermates cuprizone-containing chow for 6 weeks. The animals were then allowed to remyelinate for 3 weeks. Paraphenylenediamine staining and platelets-derived growth factor receptor α (PDGFRα) and glutathione S-transferase pi (GSTpi) immunohistochemistry were performed on corpus callosum (CC) sections for quantification of myelin and progenitor and mature oligodendrocytes, respectively. The EAE model was induced with the MOG35-55 peptide. The animals were scored daily for clinical symptoms for 30 days. Following 6 weeks of demyelination, both KL-OE mice and WT littermates demonstrated almost complete and comparable demyelination of the CC. However, the level of spontaneous remyelination was increased approximately two-fold in KL-OE mice, although no significant differences in the numbers of PDGFRα and GSTpi-positive cells were observed. Following EAE induction, Klotho overexpression did not affect the clinical scores, likely due to the different roles Klotho plays in the brain and spinal cord. Thus, increasing Klotho expression should be considered as a therapy for enhancing remyelination in the brains of individuals with multiple sclerosis.

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Astrocyte development: A Guide for the Perplexed

Molofsky

Deneen

2015

Glia

265

236

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Astrocytes are the predominant cell type in the brain and perform key functions vital to CNS physiology, including blood brain barrier formation and maintenance, synaptogenesis, neurotransmission, and metabolic regulation. To fully understand the contributions of astrocytes to brain function, it will be important to bridge the existing gap between development and physiology. In this review, we provide an overview of Astrocyte development, including recent insights into molecular mechanisms of astrocyte specification, regional patterning and proliferation. This developmental perspective is complemented with recent findings that describe the functional maturation of astrocytes and their prospective diversity. Future progress in understanding Astrocyte development will depend on the development of astrocyte- stage specific markers and tools for manipulating astrocytes without affecting neuron production. Ultimately, a mechanistic approach to Astrocyte development will be crucial to developing new treatments for the many neurodevelopmental, neurodegenerative, neuroimmune, and neoplastic diseases involving astrocyte dysfunction.

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Ascl1 controls the number and distribution of astrocytes and oligodendrocytes in the gray matter and white matter of the spinal cord

Cited by 42 publications

References 51 publications

ASCL1 regulates proliferation of NG2‐glia in the embryonic and adult spinal cord

ASCL1 regulates proliferation of NG2‐glia in the embryonic and adult spinal cord

The Anti-Aging Protein Klotho Enhances Remyelination Following Cuprizone-Induced Demyelination

Astrocyte development: A Guide for the Perplexed

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