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| Status |
Public on Dec 10, 2009 |
| Title |
Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
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 ∼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 β-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–β-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of β-catenin in the oligodendrocyte lineage in vivo and (2) findings from APCMin mice, which lack one functional copy of the endogenous Wnt pathway inhibitor APC. Together, our findings indicate that dysregulated Wnt–β-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.
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| Overall design |
12 samples total. Two variables in the experiment: genotype (wild type or Olig2cre/DA-Cat) and Developmental stage (Day 4 or Day 15). 4 phenotypes in total with 3 biological replicates for each phenotype.
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| Contributor(s) |
Rowitch D |
| Citation(s) |
19515974, 21706018 |
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| Submission date |
Dec 09, 2009 |
| Last update date |
Feb 11, 2019 |
| Contact name |
David Rowitch |
| E-mail(s) |
RowitchD@peds.ucsf.edu
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| Organization name |
University of California San Francisco
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| Department |
Neurology
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| Street address |
513 Parnassus Ave, Medical Science Building
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| City |
SAN FRANCISCO |
| State/province |
CA |
| ZIP/Postal code |
94143 |
| Country |
USA |
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| Platforms (1) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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| Samples (12)
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| GSM482060 |
spinal cord wild type at 15 days, biological replicate 1 |
| GSM482061 |
spinal cord wild type at 15 days, biological replicate 2 |
| GSM482062 |
spinal cord wild type at 15 days, biological replicate 3 |
| GSM482063 |
spinal cord Olig2cre/DA-Cat at 15 days, biological replicate 1 |
| GSM482064 |
spinal cord Olig2cre/DA-Cat at 15 days, biological replicate 2 |
| GSM482065 |
spinal cord Olig2cre/DA-Cat at 15 days, biological replicate 3 |
| GSM482066 |
spinal cord wild type at 4 days, biological replicate 1 |
| GSM482067 |
spinal cord wild type at 4 days, biological replicate 2 |
| GSM482068 |
spinal cord wild type at 4 days, biological replicate 3 |
| GSM482069 |
spinal cord Olig2cre/DA-Cat at 4 days, biological replicate 1 |
| GSM482070 |
spinal cord Olig2cre/DA-Cat at 4 days, biological replicate 2 |
| GSM482071 |
spinal cord Olig2cre/DA-Cat at 4 days, biological replicate 3 |
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| Relations |
| BioProject |
PRJNA121771 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE19403_RAW.tar |
44.2 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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