MiRNA-128 regulates the proliferation and neurogenesis of neural precursors by targeting PCM1 in the developing cortex.

Wei Zhang,Hyunsoo Shawn Je,Zhongcan Chen,Ke Zhang,Steven George Rozen,Lifeng Qiu,Hidayat Lokman,Eng King Tan,Li Zeng,Paul Jong Kim

doi:10.7554/elife.11324

Abstract

During the development, tight regulation of the expansion of neural progenitor cells (NPCs) and their differentiation into neurons is crucial for normal cortical formation and function. In this study, we demonstrate that microRNA (miR)-128 regulates the proliferation and differentiation of NPCs by repressing pericentriolar material 1 (PCM1). Specifically, overexpression of miR-128 reduced NPC proliferation but promoted NPC differentiation into neurons both in vivo and in vitro. In contrast, the reduction of endogenous miR-128 elicited the opposite effects. Overexpression of miR-128 suppressed the translation of PCM1, and knockdown of endogenous PCM1 phenocopied the observed effects of miR-128 overexpression. Furthermore, concomitant overexpression of PCM1 and miR-128 in NPCs rescued the phenotype associated with miR-128 overexpression, enhancing neurogenesis but inhibiting proliferation, both in vitro and in utero. Taken together, these results demonstrate a novel mechanism by which miR-128 regulates the proliferation and differentiation of NPCs in the developing neocortex.

Highlights

Neurogenesis, the process by which functionally integrated neurons are generated from neural progenitor cells (NPCs), involves the proliferation and neuronal fate specification of NPCs and the subsequent maturation and functional integration of the neuronal progeny into neuronal circuits (Gupta et al, 2002)
Given its importance in the development of the nervous system, neurogenesis is tightly regulated at many levels by both extrinsic and intrinsic factors (Heng et al, 2010), and its disruption has been associated with various pathologies, including autism spectrum disorders (ASDs), Treacher Collins syndrome, and various neural tube defects (Sun and Hevner, 2014)
To determine the spatial distribution of miR-128 in the developing embryonic cortex, we performed in situ hybridization (ISH) using digoxigenin (DIG)-labeled locked nucleic acid (LNA) detection probes targeted to the mature form of miR-128 (Figure 1A)

Summary

Introduction

Neurogenesis, the process by which functionally integrated neurons are generated from neural progenitor cells (NPCs), involves the proliferation and neuronal fate specification of NPCs and the subsequent maturation and functional integration of the neuronal progeny into neuronal circuits (Gupta et al, 2002). Given its importance in the development of the nervous system, neurogenesis is tightly regulated at many levels by both extrinsic and intrinsic factors (Heng et al, 2010), and its disruption has been associated with various pathologies, including autism spectrum disorders (ASDs), Treacher Collins syndrome, and various neural tube defects (Sun and Hevner, 2014). Uncovering the molecular mechanisms that underlie neurogenesis is crucial to understand the functions and plasticity of brain development and to prevent such pathologies (Sun and Hevner, 2014).

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Conclusion