Cdk5-dependent Mst3 phosphorylation and activity regulate neuronal migration through RhoA inhibition

Jing Tang; Jacque P.K. Ip; Tao Ye; Yu-Pong Ng; Wing-Ho Yung; Zhenguo Wu; Weiqun Fang; Amy K.Y. Fu; Nancy Y. Ip

doi:10.1523/JNEUROSCI.5449-13.2014

Cdk5-dependent Mst3 phosphorylation and activity regulate neuronal migration through RhoA inhibition

Jing Tang, Jacque P.K. Ip, Tao Ye, Yu-Pong Ng, Wing-Ho Yung, Zhenguo Wu, Weiqun Fang, Amy K.Y. Fu, Nancy Y. Ip

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

59 Citations (Scopus)

29 Downloads (CityUHK Scholars)

Abstract

The radial migration of newborn neurons is critical for the lamination of the cerebral cortex. Proper neuronal migration requires precise and rapid reorganization of the actin and microtubule cytoskeleton. However, the underlying signaling mechanisms controlling cytoskeletal reorganization are not well understood. Here, we show that Mst3, a serine/threonine kinase highly expressed in the developing mouse brain, is essential for radial neuronal migration and final neuronal positioning in the developing mouse neocortex. Mst3 silencing by in utero electroporation perturbed the multipolar-to-bipolar transition of migrating neurons and significantly retards radial migration. Although the kinase activity of Mst3 is essential for its functions in neuronal morphogenesis and migration, it is regulated via its phosphorylation at Ser79 by a serine/threonine kinase, cyclin-dependent kinase 5 (Cdk5). Our results show that Mst3 regulates neuronal migration through modulating the activity of RhoA, a Rho-GTPase critical for actin cytoskeletal reorganization. Mst3 phosphorylates RhoA at Ser26, thereby negatively regulating the GTPase activity of RhoA. Importantly, RhoA knockdown successfully rescues neuronal migration defect in Mst3-knockdown cortices. Our findings collectively suggest that Cdk5-Mst3 signaling regulates neuronal migration via RhoA-dependent actin dynamics. © 2014 the authors.

Original language	English
Pages (from-to)	7425-7436
Journal	The Journal of Neuroscience
Volume	34
Issue number	22
DOIs	https://doi.org/10.1523/JNEUROSCI.5449-13.2014
Publication status	Published - 2014
Externally published	Yes

Bibliographical note

Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].

Funding

This work was supported by the Research Grants Council of Hong Kong SAR (Grants HKUST660810, HKUST660711, HKUST661111, HKUST661212, and HKUST660213), the National Key Basic Research Program of China (Grant 2013CB530900), the Theme-based Research Scheme of the University Grants Committee (Grant T13-607/12-R), the Innovation and Technology Fund for State Key Laboratory (Grant ITCPT/17-9), the Shenzhen Peacock Plan, and the S.H. Ho Foundation. We thank Cara Kwong, Busma Butt, Wanting Zhong, and William Chau for excellent technical assistance; other members of the Ip laboratory, in particular Dr. Lei Shi, for helpful discussions; and Xuemin Zhang and Weihua Li (National Center of Biomedical Analysis) for providing help in mass spectrometry analysis.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Keywords

Actin
Cyclin-dependent kinase
Neuronal migration
Rho-GTPase

Publisher's Copyright Statement

COPYRIGHT TERMS OF DEPOSITED FINAL PUBLISHED VERSION FILE: This full text is made available under CC-BY-NC-SA 3.0. https://creativecommons.org/licenses/by-nc-sa/3.0/

RGC Funding Information

RGC-funded

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10.1523/JNEUROSCI.5449-13.2014

149978387.pdfFinal Published version, 6.36 MBLicence: CC BY-NC-SA

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@article{e168fc62a4d14d2298e7474453698569,

title = "Cdk5-dependent Mst3 phosphorylation and activity regulate neuronal migration through RhoA inhibition",

abstract = "The radial migration of newborn neurons is critical for the lamination of the cerebral cortex. Proper neuronal migration requires precise and rapid reorganization of the actin and microtubule cytoskeleton. However, the underlying signaling mechanisms controlling cytoskeletal reorganization are not well understood. Here, we show that Mst3, a serine/threonine kinase highly expressed in the developing mouse brain, is essential for radial neuronal migration and final neuronal positioning in the developing mouse neocortex. Mst3 silencing by in utero electroporation perturbed the multipolar-to-bipolar transition of migrating neurons and significantly retards radial migration. Although the kinase activity of Mst3 is essential for its functions in neuronal morphogenesis and migration, it is regulated via its phosphorylation at Ser79 by a serine/threonine kinase, cyclin-dependent kinase 5 (Cdk5). Our results show that Mst3 regulates neuronal migration through modulating the activity of RhoA, a Rho-GTPase critical for actin cytoskeletal reorganization. Mst3 phosphorylates RhoA at Ser26, thereby negatively regulating the GTPase activity of RhoA. Importantly, RhoA knockdown successfully rescues neuronal migration defect in Mst3-knockdown cortices. Our findings collectively suggest that Cdk5-Mst3 signaling regulates neuronal migration via RhoA-dependent actin dynamics. {\textcopyright} 2014 the authors.",

keywords = "Actin, Cyclin-dependent kinase, Neuronal migration, Rho-GTPase",

author = "Jing Tang and Ip, {Jacque P.K.} and Tao Ye and Yu-Pong Ng and Wing-Ho Yung and Zhenguo Wu and Weiqun Fang and Fu, {Amy K.Y.} and Ip, {Nancy Y.}",

note = "Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].",

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doi = "10.1523/JNEUROSCI.5449-13.2014",

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TY - JOUR

T1 - Cdk5-dependent Mst3 phosphorylation and activity regulate neuronal migration through RhoA inhibition

AU - Tang, Jing

AU - Ip, Jacque P.K.

AU - Ye, Tao

AU - Ng, Yu-Pong

AU - Yung, Wing-Ho

AU - Wu, Zhenguo

AU - Fang, Weiqun

AU - Fu, Amy K.Y.

AU - Ip, Nancy Y.

N1 - Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].

PY - 2014

Y1 - 2014

N2 - The radial migration of newborn neurons is critical for the lamination of the cerebral cortex. Proper neuronal migration requires precise and rapid reorganization of the actin and microtubule cytoskeleton. However, the underlying signaling mechanisms controlling cytoskeletal reorganization are not well understood. Here, we show that Mst3, a serine/threonine kinase highly expressed in the developing mouse brain, is essential for radial neuronal migration and final neuronal positioning in the developing mouse neocortex. Mst3 silencing by in utero electroporation perturbed the multipolar-to-bipolar transition of migrating neurons and significantly retards radial migration. Although the kinase activity of Mst3 is essential for its functions in neuronal morphogenesis and migration, it is regulated via its phosphorylation at Ser79 by a serine/threonine kinase, cyclin-dependent kinase 5 (Cdk5). Our results show that Mst3 regulates neuronal migration through modulating the activity of RhoA, a Rho-GTPase critical for actin cytoskeletal reorganization. Mst3 phosphorylates RhoA at Ser26, thereby negatively regulating the GTPase activity of RhoA. Importantly, RhoA knockdown successfully rescues neuronal migration defect in Mst3-knockdown cortices. Our findings collectively suggest that Cdk5-Mst3 signaling regulates neuronal migration via RhoA-dependent actin dynamics. © 2014 the authors.

AB - The radial migration of newborn neurons is critical for the lamination of the cerebral cortex. Proper neuronal migration requires precise and rapid reorganization of the actin and microtubule cytoskeleton. However, the underlying signaling mechanisms controlling cytoskeletal reorganization are not well understood. Here, we show that Mst3, a serine/threonine kinase highly expressed in the developing mouse brain, is essential for radial neuronal migration and final neuronal positioning in the developing mouse neocortex. Mst3 silencing by in utero electroporation perturbed the multipolar-to-bipolar transition of migrating neurons and significantly retards radial migration. Although the kinase activity of Mst3 is essential for its functions in neuronal morphogenesis and migration, it is regulated via its phosphorylation at Ser79 by a serine/threonine kinase, cyclin-dependent kinase 5 (Cdk5). Our results show that Mst3 regulates neuronal migration through modulating the activity of RhoA, a Rho-GTPase critical for actin cytoskeletal reorganization. Mst3 phosphorylates RhoA at Ser26, thereby negatively regulating the GTPase activity of RhoA. Importantly, RhoA knockdown successfully rescues neuronal migration defect in Mst3-knockdown cortices. Our findings collectively suggest that Cdk5-Mst3 signaling regulates neuronal migration via RhoA-dependent actin dynamics. © 2014 the authors.

KW - Actin

KW - Cyclin-dependent kinase

KW - Neuronal migration

KW - Rho-GTPase

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DO - 10.1523/JNEUROSCI.5449-13.2014

M3 - RGC 21 - Publication in refereed journal

C2 - 24872548

SN - 0270-6474

VL - 34

SP - 7425

EP - 7436

JO - The Journal of Neuroscience

JF - The Journal of Neuroscience

IS - 22

ER -

Cdk5-dependent Mst3 phosphorylation and activity regulate neuronal migration through RhoA inhibition

Abstract

Bibliographical note

Funding

UN SDGs

Research Keywords

Publisher's Copyright Statement

RGC Funding Information

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TBRS-ExtU-Lead: Stem Cell Strategy for Nervous System Disorders

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Cdk5-dependent Mst3 phosphorylation and activity regulate neuronal migration through RhoA inhibition

Abstract

Bibliographical note

Funding

UN SDGs

Research Keywords

Publisher's Copyright Statement

RGC Funding Information

Access Output

Other Access Options

Permanent Link

Other Files and Links

Fingerprint

Projects

TBRS-ExtU-Lead: Stem Cell Strategy for Nervous System Disorders

Cite this