title: Mapping differentiation kinetics in the mouse retina reveals an extensive period of cell cycle protein expression in post-mitotic newborn neurons.
abstract: BACKGROUND
  Knowledge of gene expression kinetics around neuronal cell birth is required to dissect mechanisms underlying progenitor fate. Here, we timed cell cycle and neuronal protein silencing/induction during cell birth in the developing murine retina.
  
  
  RESULTS
  The pan-cell cycle markers Pcna and Mcm6 were present in the post-mitotic ganglion cell layer. Although confined to the neuroblastic layer (NBL), 6-7% of Ki67(+) cells lacked six progenitor/cell cycle markers, and expressed neuronal markers. To define protein extinction/induction timing, we defined G2/M length throughout retinogenesis, which was typically 1-2 h, but <10% cells took double this time. BrdU-chase analyses revealed that at E12.5, Tubb3 (Tuj1) appeared at M-phase, followed by Calb2 and Dcx at ~2 h, Elavl2/3/4 at ~4 h, and Map2 at ~6 h after cell birth, and these times extended with embryonic age. Strikingly, Ki67 was not extinguished until up to a day after cell cycle exit, coinciding with exit from the NBL and induction of late markers such as Map1b/Uchl1/Rbfox3.
  
  
  CONCLUSIONS
  A minor population of progenitors transits slowly through G2/M and, most importantly, some cell cycle proteins are retained for an unexpectedly long period in post-mitotic neurons. The high-resolution map of cell birth kinetics reported here provides a framework to better define mechanisms that regulate neurogenesis.
authors: Genetics and Development Division, Toronto Western Research Institute, University Health Network, Toronto, Canada.
authors: Marek
authors: M
authors: Pacal
authors: Rod
authors: R
authors: Bremner
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001973:Bromodeoxyuridine; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D000089662:Doublecortin Protein; D059565:G2 Phase Cell Cycle Checkpoints / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D007091:Image Processing, Computer-Assisted; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D064151:Minichromosome Maintenance Complex Component 6; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012160:Retina / Q000166:cytology* / Q000254:growth & development; D013997:Time Factors
chemical_list: D018797:Cell Cycle Proteins; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen; C491205:Mcm6 protein, mouse; D064151:Minichromosome Maintenance Complex Component 6; D001973:Bromodeoxyuridine