Genetic evidence that Nkx2.2 and Pdgfra are major determinants of the timing of oligodendrocyte differentiation in the developing CNS.
In the central nervous system (CNS), oligodendrocyte maturation and axonal myelination occur on a predictable schedule, but the underlying timing mechanisms are largely unknown. In the present study, we demonstrate that Nkx2.2 homeodomain transcription factor is a key regulator for the timing of oligodendrocyte differentiation during development. Whereas induced expression of Nkx2.2 in early oligodendrocyte precursor cells (OPCs) causes precocious differentiation of oligodendrocytes, conditional ablation of Nkx2.2 temporally delays oligodendrocyte maturation. Moreover, Nkx2.2 can directly bind to the promoter of platelet-derived growth factor receptor alpha (Pdgfra) and repress its gene expression. Genetic ablation of Pdgfra mimics the effect of Nkx2.2 overexpression in accelerating OPC differentiation in the developing spinal cord. Together, our findings strongly suggest that Nkx2.2 functions as a major 'switch' to turn off Pdgfra signaling in OPCs and initiate the intrinsic program for oligodendrocyte differentiation.
Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY 40292, USA.
Qiang
Q
Zhu
Xiaofeng
X
Zhao
Kang
K
Zheng
Hong
H
Li
Hao
H
Huang
Zunyi
Z
Zhang
Teresa
T
Mastracci
Michael
M
Wegner
Yiping
Y
Chen
Lori
L
Sussel
Mengsheng
M
Qiu
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002490:Central Nervous System / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009186:Myelin Sheath / Q000235:genetics; D009836:Oligodendroglia / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D029961:Zebrafish Proteins
D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C000715627:Nkx2-2 protein, mouse; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish; D020796:Receptor, Platelet-Derived Growth Factor alpha
Mouse; Spinal cord; Tet-on; Transcription factor