RNA-Binding Protein FXR2 Regulates Adult Hippocampal Neurogenesis by Reducing Noggin Expression

Abstract

SUMMARY In adult mammalian brains, neurogenesis persists in the subventricular zone of the lateral ventricles (SVZ) and the dentate gyrus (DG) of the hippocampus. Although evidence suggest that adult neurogenesis in these two regions is subjected to differential regulation, the underlying mechanism is unclear. Here we show that the RNA-binding protein FXR2 specifically regulates DG neurogenesis by reducing the stability of Noggin mRNA. FXR2 deficiency leads to increased Noggin expression and subsequently reduced BMP signaling, which results in increased proliferation and altered fate specification of neural stem/progenitor cells in DG. In contrast, Noggin is not regulated by FXR2 in the SVZ, because Noggin expression is restricted to the ependymal cells of the lateral ventricles, where FXR2 is not expressed. Differential regulation of SVZ and DG stem cells by FXR2 may be a key component of the mechanism that governs the different neurogenic processes in these two adult germinal zones.

Positive feedback between RNA-binding protein HuD and transcription factor SATB1 promotes neurogenesis

“…Recombinant viral production and in vivo viral grafting using stereotaxic surgery were performed as described previously (33,42,43). In brief, 7-to 8-wkold C57B/L6 male mice were anesthetized with isofluorane and placed in a stereotactic instrument (KOPF).…”

“…For the mRNA stability assay, cultured hippocampus neurons were treated with 10 μg/mL actinomycin D (Sigma-Aldrich; A1410) to inhibit gene transcription (33) and SVZ NSCs were collected at various time intervals for RNA isolation and qPCR analysis. SATB1 and NeuroD1 mRNA levels were normalized to Gapdh.…”

“…In brief, we used the exponential function M = M 0 e −λt , where M is the amount of mRNA at time t, M0 is the amount of mRNA at time 0, and λ = (ln 2)/T 1/2 , where T 1/2 is the half-life of the mRNA. RT-PCR, qPCR, and pathway array analyses were performed using standard methods as described previously (33,43,46). The first-strand cDNA was generated by reverse transcription with random primers using a Transcriptor First-Strand cDNA Synthesis Kit (Roche; 04896866001).…”

“…S7 F-H). To validate these data, we quantified cell lineage markers using our established unbiased stereology method (32,33). Since both shSATB1-1 and 3 can knockdown SATB1 efficiently and had similar effects on NSC differentiation, we decided to focus on the shSATB1-#1 first (SI Appendix, Fig.…”

Regulation of Basal and Injury-Induced Fate Decisions of Adult Neural Precursor Cells: Focus on SOCS2 and Related Signalling Pathways

“…Inhibition of the BMP pathway increases neurogenesis initially, however it results in depletion of the NSC pool leading to decreased neurogenesis [24]. In the dentate gyrus, the RNA-binding protein FXR2 regulates neurogenesis by reducing the stability of noggin mRNA leading to an increased activation of the BMP pathway [25]. Proliferation in the SVZ is under epigenetic control via histone HZAX phosophorylation which can limit proliferation and overall neurogenesis [26].…”