Maternal embryonic leucine zipper kinase (MELK) was previously identified in a screen for genes enriched in neural progenitors. Here, we demonstrate expression of MELK by progenitors in developing and adult brain and that MELK serves as a marker for self-renewing multipotent neural progenitors (MNPs) in cultures derived from the developing forebrain and in transgenic mice. Overexpression of MELK enhances (whereas knockdown diminishes) the ability to generate neurospheres from MNPs, indicating a function in self-renewal. MELK down-regulation disrupts the production of neurogenic MNP from glial fibrillary acidic protein (GFAP)–positive progenitors in vitro. MELK expression in MNP is cell cycle regulated and inhibition of MELK expression down-regulates the expression of B-myb, which is shown to also mediate MNP proliferation. These findings indicate that MELK is necessary for proliferation of embryonic and postnatal MNP and suggest that it regulates the transition from GFAP-expressing progenitors to rapid amplifying progenitors in the postnatal brain.
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1 August 2005
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August 01 2005
Maternal embryonic leucine zipper kinase (MELK) regulates multipotent neural progenitor proliferation
Ichiro Nakano,
Ichiro Nakano
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
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Andres A. Paucar,
Andres A. Paucar
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
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Ruchi Bajpai,
Ruchi Bajpai
8The Burnham Institute, La Jolla, CA 92037
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Joseph D. Dougherty,
Joseph D. Dougherty
6Departments of The Neuroscience Graduate Program, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
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Amani Zewail,
Amani Zewail
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
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Theresa K. Kelly,
Theresa K. Kelly
6Departments of The Neuroscience Graduate Program, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
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Kevin J. Kim,
Kevin J. Kim
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
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Jing Ou,
Jing Ou
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
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Matthias Groszer,
Matthias Groszer
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
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Tetsuya Imura,
Tetsuya Imura
5Departments of Neurobiology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
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William A. Freije,
William A. Freije
7Departments of Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
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Stanley F. Nelson,
Stanley F. Nelson
7Departments of Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
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Michael V. Sofroniew,
Michael V. Sofroniew
5Departments of Neurobiology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
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Hong Wu,
Hong Wu
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
7Departments of Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
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Xin Liu,
Xin Liu
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
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Alexey V. Terskikh,
Alexey V. Terskikh
8The Burnham Institute, La Jolla, CA 92037
9Department of Life Sciences, Swiss Federal Institute of Technology, CH-1015, Lausanne, Switzerland
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Daniel H. Geschwind,
Daniel H. Geschwind
2Departments of Psychiatry, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
4Departments of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
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Harley I. Kornblum
Harley I. Kornblum
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
2Departments of Psychiatry, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
3Departments of Pediatrics, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
7Departments of Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
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Ichiro Nakano
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
Andres A. Paucar
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
Ruchi Bajpai
8The Burnham Institute, La Jolla, CA 92037
Joseph D. Dougherty
6Departments of The Neuroscience Graduate Program, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
Amani Zewail
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
Theresa K. Kelly
6Departments of The Neuroscience Graduate Program, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
Kevin J. Kim
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
Jing Ou
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
Matthias Groszer
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
Tetsuya Imura
5Departments of Neurobiology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
William A. Freije
7Departments of Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
Stanley F. Nelson
7Departments of Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
Michael V. Sofroniew
5Departments of Neurobiology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
Hong Wu
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
7Departments of Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
Xin Liu
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
Alexey V. Terskikh
8The Burnham Institute, La Jolla, CA 92037
9Department of Life Sciences, Swiss Federal Institute of Technology, CH-1015, Lausanne, Switzerland
Daniel H. Geschwind
2Departments of Psychiatry, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
4Departments of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
Harley I. Kornblum
1Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
2Departments of Psychiatry, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
3Departments of Pediatrics, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
7Departments of Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
Correspondence to Harley I. Kornblum:[email protected]
A.A. Paucar, J.D. Dougherty, and R. Bajpai contributed equally to this paper.
Abbreviations used in this paper: CNS, central nervous system; EGL, external granule cell layer; ES, embryonic stem; GFAP, glial fibrillary acidic protein; GZ, germinal zone; MELK, maternal embryonic leucine zipper kinase; MNP, multipotent neuroprogenitor; Msi1, musashi1; NCS, nucleostemin; NS, neural stem; PCMV, cytomegalovirus promoter; PMELK, MELK promoter; siRNA, small inhibitory RNA; SVZ, subventricular zone.
Received:
December 17 2004
Accepted:
June 30 2005
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2005
J Cell Biol (2005) 170 (3): 413–427.
Article history
Received:
December 17 2004
Accepted:
June 30 2005
Citation
Ichiro Nakano, Andres A. Paucar, Ruchi Bajpai, Joseph D. Dougherty, Amani Zewail, Theresa K. Kelly, Kevin J. Kim, Jing Ou, Matthias Groszer, Tetsuya Imura, William A. Freije, Stanley F. Nelson, Michael V. Sofroniew, Hong Wu, Xin Liu, Alexey V. Terskikh, Daniel H. Geschwind, Harley I. Kornblum; Maternal embryonic leucine zipper kinase (MELK) regulates multipotent neural progenitor proliferation . J Cell Biol 1 August 2005; 170 (3): 413–427. doi: https://doi.org/10.1083/jcb.200412115
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