title: Regulation of zygotic genome activation and DNA damage checkpoint acquisition at the mid-blastula transition.
abstract: Following fertilization, oviparous embryos undergo rapid, mostly transcriptionally silent cleavage divisions until the mid-blastula transition (MBT), when large-scale developmental changes occur, including zygotic genome activation (ZGA) and cell cycle remodeling, via lengthening and checkpoint acquisition. Despite their concomitant appearance, whether these changes are co-regulated is unclear. Three models have been proposed to account for the timing of (ZGA). One model implicates a threshold nuclear to cytoplasmic (N:C) ratio, another stresses the importance cell cycle elongation, while the third model invokes a timer mechanism. We show that precocious Chk1 activity in pre-MBT zebrafish embryos elongates cleavage cycles, thereby slowing the increase in the N:C ratio. We find that cell cycle elongation does not lead to transcriptional activation. Rather, ZGA slows in parallel with the N:C ratio. We show further that the DNA damage checkpoint program is maternally supplied and independent of ZGA. Although pre-MBT embryos detect damage and activate Chk2 after induction of DNA double-strand breaks, the Chk1 arm of the DNA damage response is not activated, and the checkpoint is nonfunctional. Our results are consistent with the N:C ratio model for ZGA. Moreover, the ability of precocious Chk1 activity to delay pre-MBT cell cycles indicate that lack of Chk1 activity limits checkpoint function during cleavage cycles. We propose that Chk1 gain-of-function at the MBT underlies cell cycle remodeling, whereas ZGA is regulated independently by the N:C ratio.
authors.affiliation: a Department of Biology and.
authors.forename: Maomao
authors.initials: M
authors.lastname: Zhang
authors.forename: Priyanka
authors.initials: P
authors.lastname: Kothari
authors.forename: Mary
authors.initials: M
authors.lastname: Mullins
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lampson
mesh_terms: D000818:Animals; D036703:Blastula / Q000378:metabolism* / Q000528:radiation effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D005720:Gamma Rays; D016678:Genome; D006657:Histones / Q000378:metabolism; D006918:Hydroxyurea / Q000633:toxicity; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; D011993:Recombinant Fusion Proteins; D029961:Zebrafish Proteins; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; D000071877:Checkpoint Kinase 1; D006918:Hydroxyurea
keywords: MBT, Mid-blastula Transition; ZGA, Zygotic genome activation; cell cycle checkpoints; embryogenesis; mid-blastula transition; zygotic genome activation