WNT signaling suppresses oligodendrogenesis via Ngn2-dependent direct inhibition of Olig2 expression
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MICRO REPORT
WNT signaling suppresses oligodendrogenesis via Ngn2‑dependent direct inhibition of Olig2 expression Min Jiang, Dan Yu, Binghua Xie, Hao Huang, Wenwen Lu, Mengsheng Qiu* and Zhong‑Min Dai*
Abstract Olig2 transcription factor is essential for the maintenance of neural progenitor cells (NPCs) in the pMN domain and their sequential specification into motor neurons (MNs) and oligodendrocyte precursor cells (OPCs). The expression of Olig2 rapidly declines in newly generated MNs. However, Olig2 expression persists in later-born OPCs and antago‑ nizes the expression of MN-related genes. The mechanism underlying the differential expression of Olig2 in MNs and oligodendrocytes remains unknown. Here, we report that activation of WNT/β-catenin signaling in pMN lineage cells abolished Olig2 expression coupled with a dramatic increase of Ngn2 expression. Luciferase reporter assay showed that Ngn2 inhibited Olig2 promoter activity. Overexpression of Ngn2-EnR transcription repressor blocked the expres‑ sion of Olig2 in ovo. Our results suggest that down-regulation of WNT-Ngn2 signaling contributes to oligodendrogen‑ esis from the pMN domain and the persistent Olig2 expression in OPCs. Keywords: WNT, β-catenin, Oligodendrocyte, Ngn2, Olig2 Olig2 is the key transcription factor that not only maintains the neural progenitor cells (NPCs) of pMN domain, but also regulates the sequential specification of NPCs into motor neurons (MNs) and OPCs [1–5]. Since persistent expression of Olig2 is inhibitory to post-mitotic MN genes [6], the expression of Olig2 rapidly declines in newly generated MNs, but remains high in later-born cells of oligodendrocyte lineage [2–6]. The mechanism of down-regulation of Olig2 expression in MNs remains elusive. WNT signaling is known to regulate the balance between the proliferation and differentiation of NPCs during neurogenesis [7]. It is interesting that endogenous WNT/β-catenin signaling is activated in newly generated MNs [8]. Activation of WNT/β-catenin signaling has been reported to inhibit the specification of OPCs and *Correspondence: [email protected]; [email protected] Institute of Life Sciences, Key Laboratory of Organ Development and Regeneration of Zhejiang Province, College of Life Sciences, Hangzhou Normal University, Hangzhou 310029, People’s Republic of China
astrocytes from NPCs during early stages of gliogenesis [9–11]. However, the mechanism underlying the inhibition of OPC specification from pMN NPCs by WNT/βcatenin signaling remains to be determined. Here, we utilized the Olig1Cre/+;Ctnnb1ΔEx3/+ transgenic mice to activate WNT signaling in the pMN domain. At embryonic day 12.5 (E12.5) when oligodendrogenesis commences, expression of Olig1 and Olig2 remains high in the pMN neural progenitor cells from which Pdgfra+ OPCs arise (Fig. 1a). Strikingly, in Olig1Cre/+;Ctnnb1ΔEx3/+ transgenic mice, activation of WNT signaling totally abolished the expression of Olig1, Olig2 and Pdgfra (Fig. 1a), indicating a complete inhibition of oligodendrogenesis. By co
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