Olig1 is required for noggin-induced neonatal myelin repair

Jennifer K. Sabo, Vivi Heine, John C. Silbereis, Lucas Schirmer, Steven Levison, David H. Rowitch

Research output: Contribution to journalArticle

7 Citations (Scopus)

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. Interpretation: 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.

Original languageEnglish (US)
Pages (from-to)560-571
Number of pages12
JournalAnnals of Neurology
Volume81
Issue number4
DOIs
StatePublished - Apr 1 2017

Fingerprint

Oligodendroglia
Myelin Sheath
Bone Morphogenetic Proteins
Interneurons
Wounds and Injuries
Transcription Factors
Stroke
Smad Proteins
Brain Hypoxia-Ischemia
Lateral Ventricles
Brain Diseases
Cerebral Palsy
Premature Infants
Stem Cells
Newborn Infant
Brain
Proteins
White Matter

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

Sabo, J. K., Heine, V., Silbereis, J. C., Schirmer, L., Levison, S., & Rowitch, D. H. (2017). Olig1 is required for noggin-induced neonatal myelin repair. Annals of Neurology, 81(4), 560-571. https://doi.org/10.1002/ana.24907
Sabo, Jennifer K. ; Heine, Vivi ; Silbereis, John C. ; Schirmer, Lucas ; Levison, Steven ; Rowitch, David H. / Olig1 is required for noggin-induced neonatal myelin repair. In: Annals of Neurology. 2017 ; Vol. 81, No. 4. pp. 560-571.
@article{7485ba039fc1473e9411d5ae7d1bbbc6,
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. Interpretation: 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.",
author = "Sabo, {Jennifer K.} and Vivi Heine and Silbereis, {John C.} and Lucas Schirmer and Steven Levison and Rowitch, {David H.}",
year = "2017",
month = "4",
day = "1",
doi = "10.1002/ana.24907",
language = "English (US)",
volume = "81",
pages = "560--571",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "4",

}

Sabo, JK, Heine, V, Silbereis, JC, Schirmer, L, Levison, S & Rowitch, DH 2017, 'Olig1 is required for noggin-induced neonatal myelin repair', Annals of Neurology, vol. 81, no. 4, pp. 560-571. https://doi.org/10.1002/ana.24907

Olig1 is required for noggin-induced neonatal myelin repair. / Sabo, Jennifer K.; Heine, Vivi; Silbereis, John C.; Schirmer, Lucas; Levison, Steven; Rowitch, David H.

In: Annals of Neurology, Vol. 81, No. 4, 01.04.2017, p. 560-571.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Olig1 is required for noggin-induced neonatal myelin repair

AU - Sabo, Jennifer K.

AU - Heine, Vivi

AU - Silbereis, John C.

AU - Schirmer, Lucas

AU - Levison, Steven

AU - Rowitch, David H.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - 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. Interpretation: 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.

AB - 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. Interpretation: 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.

UR - http://www.scopus.com/inward/record.url?scp=85018753239&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018753239&partnerID=8YFLogxK

U2 - 10.1002/ana.24907

DO - 10.1002/ana.24907

M3 - Article

VL - 81

SP - 560

EP - 571

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 4

ER -

Sabo JK, Heine V, Silbereis JC, Schirmer L, Levison S, Rowitch DH. Olig1 is required for noggin-induced neonatal myelin repair. Annals of Neurology. 2017 Apr 1;81(4):560-571. https://doi.org/10.1002/ana.24907