KIF20A/MKLP2 regulates the division modes of neural progenitor cells during cortical development

Anqi Geng,Meisheng Jiang,Nam Duong,Heying Zhang,Walter Tsark,Jiing-Kuan Yee,Henry Farhoodi,Runxiang Qiu,Kiyohito Murai,Qiang Lu,Jiancheng Liu,Xiwei Wu

doi:10.1038/s41467-018-05152-1

Abstract

Balanced symmetric and asymmetric divisions of neural progenitor cells (NPCs) are crucial for brain development, but the underlying mechanisms are not fully understood. Here we report that mitotic kinesin KIF20A/MKLP2 interacts with RGS3 and plays a crucial role in controlling the division modes of NPCs during cortical neurogenesis. Knockdown of KIF20A in NPCs causes dislocation of RGS3 from the intercellular bridge (ICB), impairs the function of Ephrin-B–RGS cell fate signaling complex, and leads to a transition from proliferative to differentiative divisions. Germline and inducible knockout of KIF20A causes a loss of progenitor cells and neurons and results in thinner cortex and ventriculomegaly. Interestingly, loss of function of KIF20A induces early cell cycle exit and precocious neuronal differentiation without causing substantial cytokinesis defect or apoptosis. Our results identify a RGS–KIF20A axis in the regulation of cell division and suggest a potential link of the ICB to regulation of cell fate determination.

Highlights

Balanced symmetric and asymmetric divisions of neural progenitor cells (NPCs) are crucial for brain development, but the underlying mechanisms are not fully understood
Full-length RGS3 identified a number of preys including α-tubulin and KIF20A (Supplementary Fig. 1) and the regulator of G protein signaling (RGS) domain pulled out KIF20A as the only prey
Because KIF20A was identified as a common candidate binding protein in both screens and it was known to be involved in cytokinesis[19], we characterized its potential interaction with RGS3 further

Summary

Introduction

Balanced symmetric and asymmetric divisions of neural progenitor cells (NPCs) are crucial for brain development, but the underlying mechanisms are not fully understood. 1234567890():,; During brain development, neural progenitor cells (NPCs) have to maintain a tight control on the balance between proliferation and differentiation, so that desired neural cell types (including neurons, glia, and other cells) can be produced in an appropriate order and with the correct numbers The regulation of such a fate decision in NPCs manifests in the form of symmetric (self-renewal) versus asymmetric (differentiation) cell divisions. We found that in utero electroporation (IUE)-mediated knockdown of Ephrin-B1 or its cytoplasmic binding protein PDZ-RGS3 (RGS3 isoform 1) in the mouse cortex could induce early neuronal differentiation within 24 h of cell transfection[16] This fast onset of knockdown effect prompted us to reason that the Ephrin-B/RGS signaling may be directly linked to cell division machinery, rather than modulating the outcome of NPC division via an indirect route, for example, through transcriptional regulation of downstream cell fate genes. We further present functional data implicating a key role of the RGS–KIF20A axis of interaction in cell fate determination during NPC divisions

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Results

Conclusion