The novel BTB/POZ and zinc finger factor Zbtb45 is essential for proper glial differentiation of neural and oligodendrocyte progenitor cells.
Understanding the regulatory mechanisms controlling the fate decisions of neural stem cells (NSCs) is a crucial issue to shed new light on mammalian central nervous system (CNS) development in health and disease. We have investigated a possible role for the previously uncharacterized BTB/POZ-domain containing zinc finger factor Zbtb45 in the differentiation of NSCs and postnatal oligodendrocyte precursors. In situ hybridization histochemistry and RT-qPCR analysis revealed that Zbtb45 mRNA was ubiquitously expressed in the developing CNS in mouse embryos at embryonic day (E) 12.5 and 14.5. Zbtb45 mRNA knockdown in embryonic forebrain NSCs by siRNA resulted in a rapid decrease in the expression of oligodendrocyte-characteristic genes after mitogen (FGF2) withdrawal, whereas the expression of astrocyte-associated genes such as CD44 and GFAP increased compared to control. Accordingly, the number of astrocytes was significantly increased seven days after Zbtb45 siRNA delivery to NSCs, in contrast to the numbers of neuronal and oligodendrocyte-like cells. Surprisingly, mRNA knockdown of the Zbtb45-associated factor Med31, a subunit of the Mediator complex, did not result in any detectable effect on NSC differentiation. Similar to NSCs, Zbtb45 mRNA knockdown in oligodendrocyte precursors (CG-4) reduced oligodendrocyte maturation upon mitogen withdrawal associated with down-regulation of the mRNA expression and protein levels of markers for oligodendrocytic differentiation. Zbtb45 mRNA knockdown did not significantly affect proliferation or cell death in any of the cell types. Based on these observations, we propose that Zbtb45 is a novel regulator of glial differentiation.
Linnaeus Center in Developmental Biology for Regenerative Medicine (DBRM), Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Erik
E
Södersten
Tobias
T
Lilja
Ola
O
Hermanson
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D009836:Oligodendroglia / Q000166:cytology / Q000502:physiology*; D016548:Prosencephalon / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D016415:Sequence Alignment; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers
D034741:RNA, Small Interfering; D014157:Transcription Factors; C557893:Zbtb45 protein, mouse; D016222:Fibroblast Growth Factor 2