Abstract
Efficient and accurate DNA replication is particularly critical in stem and progenitor cells for successful proliferation and survival. The replisome, an amalgam of protein complexes, is responsible for binding potential origins of replication, unwinding the double helix, and then synthesizing complimentary strands of DNA. According to current models, the initial steps of DNA unwinding and opening are facilitated by the CMG complex, which is composed of a GINS heterotetramer that connects Cdc45 with the mini-chromosome maintenance (Mcm) helicase. In this work, we provide evidence that in the absence of GINS function DNA replication is cell autonomously impaired, and we also show that gins1 and gins2 mutants exhibit elevated levels of apoptosis restricted to actively proliferating regions of the central nervous system (CNS). Intriguingly, our results also suggest that the rapid cell cycles during early embryonic development in zebrafish may not require the function of the canonical GINS complex as neither zygotic Gins1 nor Gins2 isoforms seem to be present during these stages.
Highlights
In larval zebrafish (Danio rerio), extensive cell proliferation during postembryonic stages is observed in proliferative zones of the central nervous system including the ciliary marginal zone (CMZ) at the periphery of the retina and the optic tectum (OT) stem cell niche located along the medial and caudal edges of the tectal hemispheres
Through phenotypic description of gins2 and gins1 loss-of-function mutations in zebrafish, we show that impairment of the GINS complex results in tissue-specific elevation of programmed cell
Mutants for CMG components that associate with the GINS complex show similar, localized apoptosis phenotypes (Ryu et al, 2005) but there do appear to be some differences in phenotype upon loss of function of different members of the CMG complex
Summary
In larval zebrafish (Danio rerio), extensive cell proliferation during postembryonic stages is observed in proliferative zones of the central nervous system including the ciliary marginal zone (CMZ) at the periphery of the retina and the optic tectum (OT) stem cell niche located along the medial and caudal edges of the tectal hemispheres. Both of these areas contain slow dividing neural stem cells adjacent to fast proliferating transit amplifying (TA) cell populations (Cerveny et al, 2012; Recher et al, 2013; Galant et al, 2016; Joly et al, 2016). The GINS complex, together with Cdc, acts as a scaffold for the N-tier of the helicase and is essential for helicase function (Gambus et al, 2006; Boskovic et al, 2007; Kamada et al, 2007; Sun et al, 2015; Yuan et al, 2016)
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