Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain.
Adult neurogenesis occurs throughout life in discrete regions of the adult mammalian brain. Little is known about the mechanism governing the sequential developmental process that leads to integration of new neurons from adult neural stem cells into the existing circuitry. Here, we investigated roles of Disrupted-In-Schizophrenia 1 (DISC1), a schizophrenia susceptibility gene, in adult hippocampal neurogenesis. Unexpectedly, downregulation of DISC1 leads to accelerated neuronal integration, resulting in aberrant morphological development and mispositioning of new dentate granule cells in a cell-autonomous fashion. Functionally, newborn neurons with DISC1 knockdown exhibit enhanced excitability and accelerated dendritic development and synapse formation. Furthermore, DISC1 cooperates with its binding partner NDEL1 in regulating adult neurogenesis. Taken together, our study identifies DISC1 as a key regulator that orchestrates the tempo of functional neuronal integration in the adult brain and demonstrates essential roles of a susceptibility gene for major mental illness in neuronal development, including adult neurogenesis.
Duan
Xin
X
Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.
Chang
Jay H
JH
Ge
Shaoyu
S
Faulkner
Regina L
RL
Kim
Ju Young
JY
Kitabatake
Yasuji
Y
Liu
Xiao-bo
XB
Yang
Chih-Hao
CH
Jordan
J Dedrick
JD
Ma
Dengke K
DK
Liu
Cindy Y
CY
Ganesan
Sundar
S
Cheng
Hwai-Jong
HJ
Ming
Guo-li
GL
Lu
Bai
B
Song
Hongjun
H
D000200:Action Potentials; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002465:Cell Movement; D049109:Cell Proliferation; D048429:Cell Size; D003712:Dendrites / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology; D005822:Genetic Vectors; D005838:Genotype; D006624:Hippocampus / Q000196:embryology / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D009435:Synaptic Transmission; D013997:Time Factors