title: Olig1 is required for noggin-induced neonatal myelin repair.
abstract: OBJECTIVE
  Neonatal white matter injury (NWMI) is a lesion found in preterm infants that can lead to cerebral palsy. Although antagonists of bone morphogenetic protein (BMP) signaling, such as Noggin, promote oligodendrocyte precursor cell (OPC) production after hypoxic-ischemic (HI) injury, the downstream functional targets are poorly understood. The basic helix-loop-helix protein, oligodendrocyte transcription factor 1 (Olig1), promotes oligodendrocyte (OL) development and is essential during remyelination in adult mice. Here, we investigated whether Olig1 function is required downstream of BMP antagonism for response to injury in the neonatal brain.
  
  
  METHODS
  We used wild-type and Olig1-null mice subjected to neonatal stroke and postnatal neural progenitor cultures, and we analyzed Olig1 expression in human postmortem samples from neonates that suffered HI encephalopathy (HIE).
  
  
  RESULTS
  Olig1-null neonatal mice showed significant hypomyelination after moderate neonatal stroke. Surprisingly, damaged white matter tracts in Olig1-null mice lacked Olig2+OPCs, and instead proliferating neuronal precursors and GABAergic interneurons were present. We demonstrate that Noggin-induced OPC production requires Olig1 function. In postnatal neural progenitors, Noggin governs production of OLs versus interneurons through Olig1-mediated repression of Dlx1/2 transcription factors. Additionally, we observed that Olig1 and the BMP signaling effector, phosphorylated SMADs (Sma- and Mad-related proteins) 1, 5, and 8, were elevated in the subventricular zone of human infants with HIE compared to controls.
  
  
  CONCLUSIONS
  These findings indicate that Olig1 has a critical function in regulation of postnatal neural progenitor cell production in response to Noggin. Ann Neurol 2017;81:560-571.
authors.affiliation: Department of Pediatrics, Eli and Edythe Broad Center for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Sabo
authors.affiliation: Department of Pediatrics, Eli and Edythe Broad Center for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA.
authors.forename: Vivi
authors.initials: V
authors.lastname: Heine
authors.affiliation: Department of Neuroscience, University of California San Francisco, San Francisco, CA.
authors.forename: John C
authors.initials: JC
authors.lastname: Silbereis
authors.affiliation: Eli and Edythe Broad Center for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA.|Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Lucas
authors.identifier: http://orcid.org/0000-0001-7142-4116
authors.initials: L
authors.lastname: Schirmer
authors.affiliation: Department of Neurology and Neuroscience, New Jersey Medical School, Rutgers University-New Jersey Medical School, Newark, NJ.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Levison
authors.affiliation: Department of Pediatrics, Eli and Edythe Broad Center for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA.|Department of Paediatrics, Wellcome Trust-MRC Stem Cell Institute, Cambridge University, Cambridge, United Kingdom.
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism*; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D058953:Neural Stem Cells; D009836:Oligodendroglia / Q000378:metabolism*; D020521:Stroke / Q000378:metabolism*; D000099176:Noggin Protein
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D000099176:Noggin Protein; C405707:OLIG1 protein, human; C494786:Olig1 protein, mouse