Cux2 (Cutl2) integrates neural progenitor development with cell-cycle progression during spinal cord neurogenesis.
Neurogenesis requires the coordination of neural progenitor proliferation and differentiation with cell-cycle regulation. However, the mechanisms coordinating these distinct cellular activities are poorly understood. Here we demonstrate for the first time that a Cut-like homeodomain transcription factor family member, Cux2 (Cutl2), regulates cell-cycle progression and development of neural progenitors. Cux2 loss-of-function mouse mutants exhibit smaller spinal cords with deficits in neural progenitor development as well as in neuroblast and interneuron differentiation. These defects correlate with reduced cell-cycle progression of neural progenitors coupled with diminished Neurod and p27(Kip1) activity. Conversely, in Cux2 gain-of-function transgenic mice, the spinal cord is enlarged in association with enhanced neuroblast formation and neuronal differentiation, particularly with respect to interneurons. Furthermore, Cux2 overexpression induces high levels of Neurod and p27(Kip1). Mechanistically, we discovered through chromatin immunoprecipitation assays that Cux2 binds both the Neurod and p27(Kip1) promoters in vivo, indicating that these interactions are direct. Our results therefore show that Cux2 functions at multiple levels during spinal cord neurogenesis. Cux2 initially influences cell-cycle progression in neural progenitors but subsequently makes additional inputs through Neurod and p27(Kip1) to regulate neuroblast formation, cell-cycle exit and cell-fate determination. Thus our work defines novel roles for Cux2 as a transcription factor that integrates cell-cycle progression with neural progenitor development during spinal cord neurogenesis.
Iulianella
Angelo
A
Stowers Institute for Medical Research, 1000 E. 50th Street, Kansas City, MO 64110, USA.
Sharma
Madhulika
M
Durnin
Michael
M
Vanden Heuvel
Greg B
GB
Trainor
Paul A
PA
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D019521:Body Patterning; D002453:Cell Cycle; D002454:Cell Differentiation; D002645:Chickens; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D018398:Homeodomain Proteins / Q000378:metabolism*; D007395:Interneurons / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008938:Mitosis; D008959:Models, Neurological; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D054259:Neural Tube / Q000002:abnormalities; D009474:Neurons / Q000166:cytology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport; D013116:Spinal Cord / Q000166:cytology* / Q000196:embryology; D013234:Stem Cells / Q000166:cytology*
D051792:Basic Helix-Loop-Helix Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018398:Homeodomain Proteins; C101672:Cux2 protein, mouse; C501008:Neurod1 protein, mouse