Dual control of neurogenesis by PC3 through cell cycle inhibition and induction of Math1.
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.
Canzoniere
Daniela
D
Istituto Neurobiologia e Medicina Molecolare and Istituto Biologia e Patologia Molecolare, Consiglio Nazionale delle Ricerche, 00156 Rome, Italy.
Farioli-Vecchioli
Stefano
S
Conti
Filippo
F
Ciotti
Maria Teresa
MT
Tata
Ada Maria
AM
Augusti-Tocco
Gabriella
G
Mattei
Elisabetta
E
Lakshmana
Madepalli K
MK
Krizhanovsky
Valery
V
Reeves
Steven A
SA
Giovannoni
Roberto
R
Castano
Francesca
F
Servadio
Antonio
A
Ben-Arie
Nissim
N
Tirone
Felice
F
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
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