The c-Ski family member and transcriptional regulator Corl2/Skor2 promotes early differentiation of cerebellar Purkinje cells.
Purkinje cells (PCs) provide the primary output from the cerebellar cortex, which controls movement and posture, and loss of PCs causes severe cerebellar dysfunction. The mechanisms underlying cell fate determination and early differentiation of PC remain largely unknown. Here we show that the c-Ski family member and transcriptional regulator Corl2 is required for correct differentiation of PCs. In Corl2 knock-out embryos, initial PC specification appeared largely normal, but in a subset of presumptive PCs generated near the ventral border of the PC domain, cell fate choice was compromised and cells showed a mixed identity expressing the interneuron marker Pax2 as well. Additionally, selection and maintenance of the transmitter phenotype was compromised in most developing PCs in the mutants. During later differentiation steps, induction of PC marker genes was significantly suppressed, suggesting that maturation was delayed in the absence of Corl2. Consistently, defects in migration, cell polarization and dendrite formation were observed in mutant PCs, although their axonal trajectories appeared normal. These phenotypes closely resembled those of mutants for Rora, an essential regulator of PC differentiation. However, Rora expression was not significantly changed in the Corl2 mutants, indicating that Corl2 does not simply act upstream of Rora to promote PC differentiation. ChIP experiments revealed that Corl2 bound to the promoter regions of several PC-selective genes, which are also known to be direct downstream targets of RORα. Altogether, our results identified a novel regulatory program of PC differentiation involving Corl2, which might cooperate with the RORα pathway.
Group for Neuronal Differentiation and Development, KAN Research Institute Inc., KobeMI R&D Center, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
Tomoya
T
Nakatani
Group for Neuronal Differentiation and Development, KAN Research Institute Inc., KobeMI R&D Center, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
Yasuko
Y
Minaki
Group for Transgenic Technology, KAN Research Institute Inc., KobeMI R&D Center, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
Minoru
M
Kumai
Group for Transgenic Technology, KAN Research Institute Inc., KobeMI R&D Center, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
Chiemi
C
Nitta
Group for Neuronal Differentiation and Development, KAN Research Institute Inc., KobeMI R&D Center, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan; Group for Stem Cell Technology, KAN Research Institute Inc., KobeMI R&D Center, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. Electronic address: y-ono@kan.eisai.co.jp.
Yuichi
Y
Ono
D000818:Animals; D001921:Brain / Q000196:embryology; D002454:Cell Differentiation; D019070:Cell Lineage; D002465:Cell Movement; D003712:Dendrites / Q000473:pathology / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011689:Purkinje Cells / Q000166:cytology* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D013997:Time Factors
C532058:Corl2 protein, mouse; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D012097:Repressor Proteins; C539739:Rora protein, mouse; D049452:Green Fluorescent Proteins
Cerebellum; Corl2/Skor2; Differentiation; Migration; Purkinje cell; RORα