Ulk4 Regulates Neural Stem Cell Pool.
The size of neural stem cell (NSC) pool at birth determines the starting point of adult neurogenesis. Aberrant neurogenesis is associated with major mental illness, in which ULK4 is proposed as a rare risk factor. Little is known about factors regulating the NSC pool, or function of the ULK4. Here, we showed that Ulk4(tm1a/tm1a) mice displayed a dramatically reduced NSC pool at birth. Ulk4 was expressed in a cell cycle-dependent manner and peaked in G2/M phases. Targeted disruption of the Ulk4 perturbed mid-neurogenesis and significantly reduced cerebral cortex in postnatal mice. Pathway analyses of dysregulated genes in Ulk4(tm1a/tm1a) mice revealed Ulk4 as a key regulator of cell cycle and NSC proliferation, partially through regulation of the Wnt signaling. In addition, we identified hemizygous deletion of ULK4 gene in 1.2/1,000 patients with pleiotropic symptoms including severe language delay and learning difficulties. ULK4, therefore, may significantly contribute to neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Stem Cells 2016;34:2318-2331.
Regenerative Medicine Institute, School of Medicine, National University of Ireland (NUI) Galway, Galway, Ireland.
Min
M
Liu
Department of Physiology, College of Life Science, Hebei Normal University, Shijiazhuang, People's Republic of China.
Zhenlong
Z
Guan
Center for Stem Cell Biology and Regenerative Medicine, Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, People's Republic of China.
Qin
Q
Shen
Genetics Department, Guy's & St. Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London, United Kingdom.
Frances
F
Flinter
Regenerative Medicine Institute, School of Medicine, National University of Ireland (NUI) Galway, Galway, Ireland.
Laura
L
Domínguez
Genetics Laboratories, Guy's Hospital, London, United Kingdom.
Joo Wook
JW
Ahn
Eli Lilly and Company Ltd. Erl Wood Manor, Windlesham, Surrey, United Kingdom.
David A
DA
Collier
Regenerative Medicine Institute, School of Medicine, National University of Ireland (NUI) Galway, Galway, Ireland.
Timothy
T
O'Brien
Regenerative Medicine Institute, School of Medicine, National University of Ireland (NUI) Galway, Galway, Ireland. sanbing.shen@nuigalway.
Sanbing
S
Shen
D000818:Animals; D000831:Animals, Newborn; D002453:Cell Cycle; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000473:pathology; D004622:Embryo, Mammalian / Q000166:cytology; D016195:G2 Phase; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology* / Q000201:enzymology*; D009474:Neurons / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D016196:S Phase; D060449:Wnt Signaling Pathway
C000625516:Ulk4 protein, mouse; D017346:Protein Serine-Threonine Kinases
Cell cycle; Copy number variations; Neural progenitor; Neural stem cells; Neurogenesis; RNA sequencing; Ulk4; Wnt signaling