Ascl1 is required for oligodendrocyte development in the spinal cord.
Development of oligodendrocytes, myelin-forming glia in the central nervous system (CNS), proceeds on a protracted schedule. Specification of oligodendrocyte progenitors (OLPs) begins early in development, whereas their terminal differentiation occurs at late embryonic and postnatal periods. How these distinct steps are controlled remains unclear. Our previous study demonstrated an important role of the helix-loop-helix (HLH) transcription factor Ascl1 in early generation of OLPs in the developing spinal cord. Here, we show that Ascl1 is also involved in terminal differentiation of oligodendrocytes late in development. Ascl1-/- mutant mice showed a deficiency in differentiation of myelin-expressing oligodendrocytes at birth. In vitro culture studies demonstrate that the induction and maintenance of co-expression of Olig2 and Nkx2-2 in OLPs, and thyroid hormone-responsive induction of myelin proteins are impaired in Ascl1-/- mutants. Gain-of-function studies further showed that Ascl1 collaborates with Olig2 and Nkx2-2 in promoting differentiation of OLPs into oligodendrocytes in vitro. Overexpression of Ascl1, Olig2 and Nkx2-2 alone stimulated the specification of OLPs, but the combinatorial action of Ascl1 and Olig2 or Nkx2-2 was required for further promoting their differentiation into oligodendrocytes. Thus, Ascl1 regulates multiple aspects of oligodendrocyte development in the spinal cord.
Sugimori
Michiya
M
Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Nagao
Motoshi
M
Parras
Carlos M
CM
Nakatani
Hiroko
H
Lebel
Mélanie
M
Guillemot
François
F
Nakafuku
Masato
M
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D029961:Zebrafish Proteins
D051792:Basic Helix-Loop-Helix Proteins; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D014157:Transcription Factors; D029961:Zebrafish Proteins; C499317:Ascl1 protein, mouse; C499318:Ascl1 protein, rat; C000715627:Nkx2-2 protein, mouse; C000715628:Nkx2-2 protein, rat; C512773:Olig2 protein, mouse; C522729:Olig2 protein, rat; C000715630:nkx2.2b protein, zebrafish