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Published 1 August 2005. doi:10.1083/jcb.200412115
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 3, 413-427
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Article

 Maternal embryonic leucine zipper kinase (MELK) regulates multipotent neural progenitor proliferation

Ichiro Nakano1, Andres A. Paucar1, Ruchi Bajpai8, Joseph D. Dougherty6, Amani Zewail1, Theresa K. Kelly6, Kevin J. Kim1, Jing Ou1, Matthias Groszer1, Tetsuya Imura5, William A. Freije7, Stanley F. Nelson7, Michael V. Sofroniew5, Hong Wu1,7, Xin Liu1, Alexey V. Terskikh8,9, Daniel H. Geschwind2,4, and Harley I. Kornblum1,2,3,7

1 Departments of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
2 Departments of Psychiatry, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
3 Departments of Pediatrics, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
4 Departments of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
5 Departments of Neurobiology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
6 Departments of The Neuroscience Graduate Program, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
7 Departments of Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095
8 The Burnham Institute, La Jolla, CA 92037
9 Department of Life Sciences, Swiss Federal Institute of Technology, CH-1015, Lausanne, Switzerland

Correspondence to Harley I. Kornblum:hkornblum{at}mednet.ucla.edu

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.

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.


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