Abstract
Mammalian tissue-specific stem cells and progenitors demonstrate differential DNA damage response. Neural progenitors in dentate gyrus of the hippocampus are known to undergo apoptosis after irradiation. Using a mouse model of hippocampal neuronal development, we characterized the apoptosis sensitivity of the different neural progenitor subpopulations in adult mouse dentate gyrus after irradiation. Two different bromodeoxyuridine incorporation paradigms were used for cell fate mapping. We identified two apoptosis sensitive neural progenitor subpopulations after irradiation. The first represented non-proliferative and non-newborn neuroblasts and immature neurons that expressed doublecortin, calretinin or both. The second consisted of proliferative intermediate neural progenitors. The putative radial glia-like neural stem cells or type-1 cells, regardless of proliferation status, were apoptosis resistant after irradiation. There was no evidence of radiation-induced apoptosis in the absence of the Trp53 (p53) gene but absence of Cdkn1a (p21) did not alter the apoptotic response. Upregulation of nuclear p53 was observed in neuroblasts after irradiation. We conclude that adult hippocampal neural progenitors may demonstrate differential p53-dependent apoptosis sensitivity after irradiation.
Highlights
Multipotent neural progenitor cells (NPCs), or stem cells, are present in the adult central nervous system (CNS)
The present results provide no evidence that type-1 cells or neural stem cells, regardless of whether they are quiescent or proliferating, are susceptible to early apoptotic death or other modes of cell death within 24 h after irradiation
We showed that immature neurons by the time they expressed neuronal nuclei (NeuN) became resistant to apoptosis after irradiation
Summary
Multipotent neural progenitor cells (NPCs), or stem cells, are present in the adult central nervous system (CNS). TThheerree iiss nnoo eevviiddeennccee ffoorr pp5533 iimmmmuunnoorreeaaccttiivviittyy iinn ddeennttaattee ggyyrruuss ooff nnoonn--iirrrraaddiiaatteedd mmiiccee ((AA));; aafftteerr iirrrraaddiiaattiioonn,, pp5533 nnuucclleeaarr iimmmmuunnoorreeaaccttiivviittyy iiss sseeeenn iinn ddeennttaattee ggyyrruuss aatt 88 hh ((((BB)),, pp5533,, rreedd;; DDCCXX,, ggrreeeenn;; DDAAPPII,, bblluuee)),, aanndd ssoommee pp5533 iimmmmuunnoorreeaaccttiivvee cceellllss aarree DDCCXX ppoossiittiivvee ((((BB)),, mmeerrggeedd,, aarrrrooww,, iinnsseett));; cceellllss iimmmmuunnoorreeaaccttiivvee ffoorr pp5533 ddoo nnoott eexxpprreessss nneessttiinn oorr GGFFAAPP ((((CC)),, ccoonnttrrooll;; ((DD)),, 55 GGyy;; pp5533,, ggrreeeenn;; nneessttiinn,,rreedd;;GGFFAAPP,, wwhhiittee;; DDAAPPII,, bblluuee;; aarrrroowwss));;tthheerreeiissnnoopp2211imimmmuunnooreraecatcitvivitiytyobosbesrevrevdedininnonno-nir-riarrdaidatiaedteddednetantteatgeygruysru; isn;cirnecarseeasine pin21p2n1uncluecalreaimr immumnuorneoarcetaivctitiyvitiys siseesneeant a8t h8 hafateftreririrrardaidaitaiotinon(((E()E,)0, 0GGyy; ;(F(F),),55GGyy;;pp2211,, rreedd;; DDCCXX,, ggrreeeenn;; DDAAPPII,, bblluuee;; ((GG));; 00 GGyy;; ((HH)),, 55 GGyy,, pp2211,, ggrreeeenn;; nneessttiinn,, rreedd;; GGFFAAPP,, wwhhiittee;; DDAAPPII,, bblluuee)). Neural stem cells or type-1 cells, regardless of their proliferating status, do not undergo apoptosis in response to DNA damage after irradiation These findings suggest that NPCs in adult dentate gyrus have differential p53 dependent apoptotic response after DNA damage
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