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

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

doi:10.1038/s41467-017-02720-9

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

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

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

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.

Original language	English
Article number	401
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-02720-9
State	Published - Dec 1 2018

Bibliographical note

Publisher Copyright:
© 2018 The Author(s).

Funding

We thank members of the W.L. Laboratory for insightful discussions; David Huang (Keck School of Medicine, USC) and Ellen XinYang (University of Buffalo, New York) for technical advice, and Jernej Ule and Cristina Militti (Department of Molecular Neuroscience, UCL Institute of Neurology) for plasmids and online data set (GSE52447). The work was supported by National Natural Science Foundation of China Grant 31530027, 31470779 and National Institutes of Health Grant R01 NS067213-01A1. B.-S. M. was supported by postdoctoral fellowship from the California Institute for Regenerative Medicine (CIRM) (No. TG2-01161).

Funders	Funder number
National Institutes of Health (NIH)
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	R01NS067213
California Institute for Regenerative Medicine
National Natural Science Foundation of China (NSFC)	31530027, 31470779

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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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.",

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

Abstract

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