title: Dual control of neurogenesis by PC3 through cell cycle inhibition and induction of Math1.
abstract: Growing evidence indicates that cell cycle arrest and neurogenesis are highly coordinated and interactive processes, governed by cell cycle genes and neural transcription factors. The gene PC3 (Tis21/BTG2) is expressed in the neuroblast throughout the neural tube and inhibits cell cycle progression at the G1 checkpoint by repressing cyclin D1 transcription. We generated inducible mouse models in which the expression of PC3 was upregulated in neuronal precursors of the neural tube and of the cerebellum. These mice exhibited a marked increase in the production of postmitotic neurons and impairment of cerebellar development. Cerebellar granule precursors of PC3 transgenic mice displayed inhibition of cyclin D1 expression and a strong increase in the expression of Math1, a transcription factor required for their differentiation. Furthermore, PC3, encoded by a recombinant adenovirus, also induced Math1 in postmitotic granule cells in vitro and stimulated the Math1 promoter activity. In contrast, PC3 expression was unaffected in the cerebellar primordium of Math1 null mice, suggesting that PC3 acts upstream to Math1. As a whole, our data suggest that cell cycle exit of cerebellar granule cell precursors and the onset of cerebellar neurogenesis are coordinated by PC3 through transcriptional control of cyclin D1 and Math1, respectively.
authors.affiliation: Istituto Neurobiologia e Medicina Molecolare and Istituto Biologia e Patologia Molecolare, Consiglio Nazionale delle Ricerche, 00156 Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Canzoniere
authors.forename: Stefano
authors.initials: S
authors.lastname: Farioli-Vecchioli
authors.forename: Filippo
authors.initials: F
authors.lastname: Conti
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Ciotti
authors.forename: Ada Maria
authors.initials: AM
authors.lastname: Tata
authors.forename: Gabriella
authors.initials: G
authors.lastname: Augusti-Tocco
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mattei
authors.forename: Madepalli K
authors.initials: MK
authors.lastname: Lakshmana
authors.forename: Valery
authors.initials: V
authors.lastname: Krizhanovsky
authors.forename: Steven A
authors.initials: SA
authors.lastname: Reeves
authors.forename: Roberto
authors.initials: R
authors.lastname: Giovannoni
authors.forename: Francesca
authors.initials: F
authors.lastname: Castano
authors.forename: Antonio
authors.initials: A
authors.lastname: Servadio
authors.forename: Nissim
authors.initials: N
authors.lastname: Ben-Arie
authors.forename: Felice
authors.initials: F
authors.lastname: Tirone
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D004392:Dwarfism / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D005804:Genes, Lethal; D016147:Genes, Tumor Suppressor; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C500943:Atoh1 protein, mouse; C489435:Btg2 protein, mouse; C070114:BTG2 protein, human