Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) regulates growth and patterning of the postnatal mouse cerebellum.
COUP-TFII (also known as Nr2f2), a member of the nuclear orphan receptor superfamily, is expressed in several regions of the central nervous system (CNS), including the ventral thalamus, hypothalamus, midbrain, pons, and spinal cord. To address the function of COUP-TFII in the CNS, we generated conditional COUP-TFII knockout mice using a tissue-specific NSE-Cre recombinase. Ablation of COUP-TFII in the brain resulted in malformation of the lobule VI in the cerebellum and a decrease in differentiation of cerebellar neurons and cerebellar growth. The decrease in cerebellar growth in NSE(Cre/+)/CII(F/F) mice is due to reduced proliferation and increased apoptosis in granule cell precursors (GCPs). Additional studies demonstrated that insulin like growth factor 1 (IGF-1) expression was reduced in the cerebellum of NSE(Cre/+)/CII(F/F) mice, thereby leading to decreased Akt1 and GSK-3beta activities, and the reduced expression of mTOR. Using ChIP assays, we demonstrated that COUP-TFII was recruited to the promoter region of IGF-1 in a Sp1-dependent manner. In addition, dendritic branching of Purkinje cells was decreased in the mutant mice. Thus, our results indicate that COUP-TFII regulates growth and maturation of the mouse postnatal cerebellum through modulation of IGF-1 expression.
Kim
Bum Jun
BJ
Department of Molecular and Cellular Biology and Development Program, Baylor College of Medicine, Houston, TX 77030, USA.
Takamoto
Norio
N
Yan
Jun
J
Tsai
Sophia Y
SY
Tsai
Ming-Jer
MJ
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D019521:Body Patterning; D051837:COUP Transcription Factor II / Q000235:genetics / Q000378:metabolism*; D064032:Calbindin 2; D064026:Calbindins; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002531:Cerebellum / Q000033:anatomy & histology* / Q000254:growth & development* / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D046509:Tissue Culture Techniques
D051837:COUP Transcription Factor II; D064032:Calbindin 2; D064026:Calbindins; D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins; D034741:RNA, Small Interfering; D064030:S100 Calcium Binding Protein G; D007334:Insulin-Like Growth Factor I; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; C546843:mTOR protein, mouse; C514862:Akt1 protein, mouse; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3