Hedgehog-dependent oligodendrocyte lineage specification in the telencephalon.
In the caudal neural tube, oligodendrocyte progenitors (OLPs) originate in the ventral neuroepithelium under the influence of Sonic hedgehog (SHH), then migrate throughout the spinal cord and brainstem before differentiating into myelin-forming cells. We present evidence that oligodendrogenesis in the anterior neural tube follows a similar pattern. We show that OLPs in the embryonic mouse forebrain express platelet-derived growth factor alpha-receptors (PDGFRA), as they do in more caudal regions. They first appear within a region of anterior hypothalamic neuroepithelium that co-expresses mRNA encoding SHH, its receptor PTC1 (PTCH) and the transcription factors OLIG1, OLIG2 and SOX10. Pdgfra-positive progenitors later spread through the forebrain into areas where Shh is not expressed, including the cerebral cortex. Cyclopamine inhibited OLP development in cultures of mouse basal forebrain, suggesting that hedgehog (HH) signalling is obligatory for oligodendrogenesis in the ventral telencephalon. Moreover, Pdgfra-positive progenitors did not appear on schedule in the ventral forebrains of Nkx2.1 null mice, which lack the telencephalic domain of Shh expression. However, OLPs did develop in cultures of Nkx2.1(-/-) basal forebrain and this was blocked by cyclopamine. OLPs also developed in neocortical cultures, even though Shh transcripts could not be detected in the embryonic cortex. Here, too, the appearance of OLPs was suppressed by cyclopamine. In keeping with these findings, we detected mRNA encoding SHH and Indian hedgehog (IHH) in both Nkx2.1(-/-) basal forebrain cultures and neocortical cultures. Overall, the data are consistent with the idea that OLPs in the telencephalon, possibly even some of those in the cortex, develop under the influence of SHH in the ventral forebrain.
Tekki-Kessaris
N
N
Wolfson Institute for Biomedical Research, The Cruciform Building, University College London, Gower Street, London WC1E 6AE, UK.
Woodruff
R
R
Hall
A C
AC
Gaffield
W
W
Kimura
S
S
Stiles
C D
CD
Rowitch
D H
DH
Richardson
W D
WD
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics; D015870:Gene Expression; D005807:Genes, Overlapping; D053823:Hedgehog Proteins; D006609:High Mobility Group Proteins / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000166:cytology*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D016548:Prosencephalon / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D011956:Receptors, Cell Surface; D055757:SOXE Transcription Factors; D013234:Stem Cells / Q000166:cytology*; D013687:Telencephalon / Q000166:cytology* / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D006609:High Mobility Group Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011506:Proteins; D020796:Receptor, Platelet-Derived Growth Factor alpha; D011956:Receptors, Cell Surface; D055757:SOXE Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; C494786:Olig1 protein, mouse; C498633:Olig1 protein, rat; C512773:Olig2 protein, mouse; C000606236:PTCH1 protein, human; C000606240:Ptch1 protein, mouse; C000606239:Ptch1 protein, rat; C509239:SHH protein, human; C527924:Sox10 protein, mouse; C527925:Sox10 protein, rat