Maternal embryonic leucine zipper kinase (MELK) regulates multipotent neural progenitor proliferation.
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.
Nakano
Ichiro
I
Department of Pharmacology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095, USA.
Paucar
Andres A
AA
Bajpai
Ruchi
R
Dougherty
Joseph D
JD
Zewail
Amani
A
Kelly
Theresa K
TK
Kim
Kevin J
KJ
Ou
Jing
J
Groszer
Matthias
M
Imura
Tetsuya
T
Freije
William A
WA
Nelson
Stanley F
SF
Sofroniew
Michael V
MV
Wu
Hong
H
Liu
Xin
X
Terskikh
Alexey V
AV
Geschwind
Daniel H
DH
Kornblum
Harley I
HI
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D015534:Trans-Activators / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; C499306:Mybl2 protein, mouse; D012333:RNA, Messenger; D015534:Trans-Activators; C108524:Melk protein, mouse; D017346:Protein Serine-Threonine Kinases