title: TAp73 acts via the bHLH Hey2 to promote long-term maintenance of neural precursors.
abstract: Increasing evidence suggests that deficits in adult stem cell maintenance cause aberrant tissue repair and premature aging [1]. While the mechanisms regulating stem cell longevity are largely unknown, recent studies have implicated p53 and its family member p63. Both proteins regulate organismal aging [2-4] as well as survival and self-renewal of tissue stem cells [5-9]. Intriguingly, haploinsufficiency for a third family member, p73, causes age-related neurodegeneration [10]. While this phenotype is at least partially due to loss of the ΔNp73 isoform, a potent neuronal prosurvival protein [11-16], a recent study showed that mice lacking the other p73 isoform, TAp73, have perturbations in the hippocampal dentate gyrus [17], a major neurogenic site in the adult brain. These findings, and the link between the p53 family, stem cells, and aging, suggest that TAp73 might play a previously unanticipated role in maintenance of neural stem cells. Here, we have tested this hypothesis and show that TAp73 ensures normal adult neurogenesis by promoting the long-term maintenance of neural stem cells. Moreover, we show that TAp73 does this by transcriptionally regulating the bHLH Hey2, which itself promotes neural precursor maintenance by preventing premature differentiation.
authors.affiliation: Cell Biology, Hospital for Sick Children, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fujitani
authors.forename: Gonzalo I
authors.initials: GI
authors.lastname: Cancino
authors.forename: Chandrasagar B
authors.initials: CB
authors.lastname: Dugani
authors.forename: Ian C G
authors.initials: IC
authors.lastname: Weaver
authors.forename: Andrée
authors.initials: A
authors.lastname: Gauthier-Fisher
authors.forename: Annie
authors.initials: A
authors.lastname: Paquin
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Wojtowicz
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D018891:Dentate Gyrus / Q000166:cytology / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009830:Olfactory Bulb / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016222:Fibroblast Growth Factor 2; D009687:Nuclear Proteins; D012097:Repressor Proteins; C485778:Hey2 protein, mouse; C454920:delta Np73, mouse