title: Impaired terminal differentiation of hippocampal granule neurons and defective contextual memory in PC3/Tis21 knockout mice.
abstract: Neurogenesis in the dentate gyrus of the adult hippocampus has been implicated in neural plasticity and memory, but the molecular mechanisms controlling the proliferation and differentiation of newborn neurons and their integration into the synaptic circuitry are still largely unknown. To investigate this issue, we have analyzed the adult hippocampal neurogenesis in a PC3/Tis21-null mouse model. PC3/Tis21 is a transcriptional co-factor endowed with antiproliferative and prodifferentiative properties; indeed, its upregulation in neural progenitors has been shown to induce exit from cell cycle and differentiation. We demonstrate here that the deletion of PC3/Tis21 causes an increased proliferation of progenitor cells in the adult dentate gyrus and an arrest of their terminal differentiation. In fact, in the PC3/Tis21-null hippocampus postmitotic undifferentiated neurons accumulated, while the number of terminally differentiated neurons decreased of 40%. As a result, PC3/Tis21-null mice displayed a deficit of contextual memory. Notably, we observed that PC3/Tis21 can associate to the promoter of Id3, an inhibitor of proneural gene activity, and negatively regulates its expression, indicating that PC3/Tis21 acts upstream of Id3. Our results identify PC3/Tis21 as a gene required in the control of proliferation and terminal differentiation of newborn neurons during adult hippocampal neurogenesis and suggest its involvement in the formation of contextual memories.
authors.affiliation: Institute of Neurobiology and Molecular Medicine, Consiglio Nazionale delle Ricerche, Fondazione S.Lucia, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Farioli-Vecchioli
authors.forename: Daniele
authors.initials: D
authors.lastname: Saraulli
authors.forename: Marco
authors.initials: M
authors.lastname: Costanzi
authors.forename: Luca
authors.initials: L
authors.lastname: Leonardi
authors.forename: Irene
authors.initials: I
authors.lastname: Cinà
authors.forename: Laura
authors.initials: L
authors.lastname: Micheli
authors.forename: Michele
authors.initials: M
authors.lastname: Nutini
authors.forename: Patrizia
authors.initials: P
authors.lastname: Longone
authors.forename: S Paul
authors.initials: SP
authors.lastname: Oh
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cestari
authors.forename: Felice
authors.initials: F
authors.lastname: Tirone
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D001522:Behavior, Animal; D002454:Cell Differentiation; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D003213:Conditioning, Psychological; D003594:Cytoplasmic Granules / Q000378:metabolism*; D018891:Dentate Gyrus / Q000473:pathology; D005239:Fear; D016193:G1 Phase; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D017874:Immediate-Early Proteins / Q000378:metabolism*; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics; D008568:Memory; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D016716:PC12 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D013234:Stem Cells / Q000166:cytology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C489435:Btg2 protein, mouse; D017874:Immediate-Early Proteins; D051796:Inhibitor of Differentiation Proteins; D025521:Tumor Suppressor Proteins; C067679:Idb3 protein, mouse