Disruption of neurogenesis and cortical development in transgenic mice misexpressing Olig2, a gene in the Down syndrome critical region.
The basic helix-loop-helix (bHLH) transcription factor Olig2 is crucial for mammalian central nervous system development. Human ortholog OLIG2 is located in the Down syndrome critical region in trisomy 21. To investigate the effect of Olig2 misexpression on brain development, we generated a developmentally regulated Olig2-overexpressing transgenic line with a Cre/loxP system. The transgenic mice with Olig2 misexpression in cortical neural stem/progenitor cells exhibited microcephaly, cortical dyslamination, hippocampus malformation, and profound motor deficits. Ectopic misexpression of Olig2 impaired cortical progenitor proliferation and caused precocious cell cycle exit. Massive neuronal cell death was detected in the developing cortex of Olig2-misexpressing mice. In addition, Olig2 misexpression led to a significant downregulation of neuronal specification factors including Ngn1, Ngn2 and Pax6, and a defect in cortical neurogenesis. Chromatin-immunoprecipitation and sequencing (ChIP-Seq) analysis indicates that Olig2 directly targets the promoter and/or enhancer regions of Nfatc4, Dscr1/Rcan1 and Dyrk1a, the critical neurogenic genes that contribute to Down syndrome phenotypes, and inhibits their expression. Together, our study suggests that Olig2 misexpression in neural stem cells elicits neurogenesis defects and neuronal cell death, which may contribute to developmental disorders including Down syndrome, where OLIG2 is triplicated on chromosomal 21.
Department of Pediatrics, West China Second Hospital, Sichuan University, Chengdu, 610041, PR China; Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA; Key Laboratory of Obstetrics & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, 610041, PR China.
Wei
W
Liu
Department of Pediatrics, West China Second Hospital, Sichuan University, Chengdu, 610041, PR China.
Hui
H
Zhou
Department of Pediatrics, West China Second Hospital, Sichuan University, Chengdu, 610041, PR China.
Lei
L
Liu
Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA.
Chuntao
C
Zhao
Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA.
Yaqi
Y
Deng
Department of Pediatrics, West China Second Hospital, Sichuan University, Chengdu, 610041, PR China.
Lina
L
Chen
Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA.
Laiman
L
Wu
Department of Developmental Biology, University of Texas Southwestern Medical Center, TX 75390, USA.
Nicole
N
Mandrycky
Department of Psychology, University of Texas, Arlington, TX 76019, USA.
Christopher T
CT
McNabb
Department of Psychology, University of Texas, Arlington, TX 76019, USA.
Yuanbo
Y
Peng
Department of Psychology, University of Texas, Arlington, TX 76019, USA.
Perry N
PN
Fuchs
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Jie
J
Lu
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Volney
V
Sheen
Institute of Developmental and Regenerative Biology, Key Laboratory of Organ Development and Regeneration of Zhejiang Province, College of Life Sciences, Hangzhou Normal University, Hangzhou, 310029, PR China; Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY 40292, USA.
Mengsheng
M
Qiu
Department of Pediatrics, West China Second Hospital, Sichuan University, Chengdu, 610041, PR China; Key Laboratory of Obstetrics & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, 610041, PR China.
Meng
M
Mao
Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA; Key Laboratory of Obstetrics & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, 610041, PR China; Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, 201102, PR China. Electronic address: richard.lu@cchmc.org.
Q Richard
QR
Lu
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D064026:Calbindins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002540:Cerebral Cortex / Q000196:embryology / Q000254:growth & development / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics* / Q000473:pathology*; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D018398:Homeodomain Proteins / Q000378:metabolism; D007395:Interneurons / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D050809:POU Domain Factors / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D018911:Trinucleotide Repeats / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D064026:Calbindins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D050809:POU Domain Factors; D010320:Parvalbumins; D012097:Repressor Proteins; D014157:Transcription Factors; C501070:RBBP8 protein, mouse; C000624101:Cux1 protein, mouse; C490641:Etv1 protein, mouse; C405708:OLIG2 protein, human; C074065:Pou3f3 protein, mouse
Cortical development; Cortical progenitor proliferation; Down syndrome; Neural cell death; Neurogenesis; Olig2