Doublecortin-like kinase controls neurogenesis by regulating mitotic spindles and M phase progression.
The mechanisms controlling neurogenesis during brain development remain relatively unknown. Through a differential protein screen with developmental versus mature neural tissues, we identified a group of developmentally enriched microtubule-associated proteins (MAPs) including doublecortin-like kinase (DCLK), a protein that shares high homology with doublecortin (DCX). DCLK, but not DCX, is highly expressed in regions of active neurogenesis in the neocortex and cerebellum. Through a dynein-dependent mechanism, DCLK regulates the formation of bipolar mitotic spindles and the proper transition from prometaphase to metaphase during mitosis. In cultured cortical neural progenitors, DCLK RNAi Lentivirus disrupts the structure of mitotic spindles and the progression of M phase, causing an increase of cell-cycle exit index and an ectopic commitment to a neuronal fate. Furthermore, both DCLK gain and loss of function in vivo specifically promote a neuronal identity in neural progenitors. These data provide evidence that DCLK controls mitotic division by regulating spindle formation and also determines the fate of neural progenitors during cortical neurogenesis.
Shu
Tianzhi
T
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Tseng
Huang-Chun
HC
Sapir
Tamar
T
Stern
Patrick
P
Zhou
Ying
Y
Sanada
Kamon
K
Fischer
Andre
A
Coquelle
Frédéric M
FM
Reiner
Orly
O
Tsai
Li-Huei
LH
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology; D000089662:Doublecortin Protein; D000089742:Doublecortin-Like Kinases; D004398:Dyneins / Q000502:physiology; D047108:Embryonic Development / Q000502:physiology; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000502:physiology; D008938:Mitosis / Q000502:physiology; D009420:Nervous System / Q000196:embryology*; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D049468:Prometaphase / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D008941:Spindle Apparatus / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism
C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D000089742:Doublecortin-Like Kinases; C485525:Dclk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004398:Dyneins