Kruppel-like factor 4-dependent Staufen1-mediated mRNA decay regulates cortical neurogenesis

Byoung-San Moon,Wange Lu,Mingyang Cai,Jinlun Bai,Chunming Liu,Jiandang Shi

doi:10.1038/s41467-017-02720-9

Abstract

Kruppel-like factor 4 (Klf4) is a zinc-finger-containing protein that plays a critical role in diverse cellular physiology. While most of these functions attribute to its role as a transcription factor, it is postulated that Klf4 may play a role other than transcriptional regulation. Here we demonstrate that Klf4 loss in neural progenitor cells (NPCs) leads to increased neurogenesis and reduced self-renewal in mice. In addition, Klf4 interacts with RNA-binding protein Staufen1 (Stau1) and RNA helicase Ddx5/17. They function together as a complex to maintain NPC self-renewal. We report that Klf4 promotes Stau1 recruitment to the 3′-untranslated region of neurogenesis-associated mRNAs, increasing Stau1-mediated mRNA decay (SMD) of these transcripts. Stau1 depletion abrogated SMD of target mRNAs and rescued neurogenesis defects in Klf4-overexpressing NPCs. Furthermore, Ddx5/17 knockdown significantly blocked Klf4-mediated mRNA degradation. Our results highlight a novel molecular mechanism underlying stability of neurogenesis-associated mRNAs controlled by the Klf4/Ddx5/17/Stau1 axis during mammalian corticogenesis.

Highlights

Kruppel-like factor 4 (Klf4) is a zinc-finger-containing protein that plays a critical role in diverse cellular physiology
The depletion of Klf[4] gene expression is confirmed in neural progenitor cells (NPCs) at theventricular zone of klf[4] conditional knockout (cKO) (Nescre;Klffl/fl) mice in vivo and cultured NPCs derived from the mice in vitro using immunochemistry and quantitative PCR analysis (Supplementary Fig. 1c–f)
Immunohistochemical analysis of forebrain regions of embryonic cortices derived from wild-type (Klf4fl/+) and klf[4] cKO (Nescre;Klffl/fl) mice revealed an increase in the number of cells positive for Tuj[1], an immature neuronal marker in Klf[4] cKO versus wild-type controls (Fig. 1a; Supplementary Fig. 2a, b)

Summary

Introduction

Kruppel-like factor 4 (Klf4) is a zinc-finger-containing protein that plays a critical role in diverse cellular physiology. Klf[4] interacts with RNA-binding protein Staufen[1] (Stau1) and RNA helicase Ddx5/17 They function together as a complex to maintain NPC self-renewal. Kruppel-like factor 4 (Klf4) is a zinc-finger-containing transcription factor that plays a critical role in various biological processes, including proliferation, differentiation, and apoptosis[8]. It was first characterized as a regulator of epithelial cell maturation in the skin[9,10] and goblet cell differentiation in the colon[11]. Stau[1] recognizes SBSs located sufficiently downstream of a translation termination codon and recruits UPF1 to trigger mRNA decay[32]

Methods

Results

Conclusion