A short G1 phase is an intrinsic determinant of naïve embryonic stem cell pluripotency

Abstract

A short G1 phase is a characteristic feature of mouse embryonic stem cells (ESCs). To determine if there is a causal relationship between G1 phase restriction and pluripotency, we made use of the Fluorescence Ubiquitination Cell Cycle Indicator (FUCCI) reporter system to FACS-sort ESCs in the different cell cycle phases. Hence, the G1 phase cells appeared to be more susceptible to differentiation, particularly when ESCs self-renewed in the naïve state of pluripotency. Transitions from ground to naïve, then from naïve to primed states of pluripotency were associated with increased durations of the G1 phase, and cyclin E-mediated alteration of the G1/S transition altered the balance between self-renewal and differentiation. LIF withdrawal resulted in a lengthening of the G1 phase in naïve ESCs, which occurred prior to the appearance of early lineage-specific markers, and could be reversed upon LIF supplementation. We concluded that the short G1 phase observed in murine ESCs was a determinant of naïve pluripotency and was partially under the control of LIF signaling.

Restricted expression of cdc25a in the tailbud is essential for formation of the zebrafish posterior body

“…Thus, the precise control of the cell cycle by regulating cdc25 expression is essential for the normal process of muscle differentiation and establishing the proper length of the embryo. While much recent work in embryonic stem cells and Xenopus has emphasized the regulation of G1 phase in controlling differentiation (Richard-Parpaillon et al 2004;Coronado et al 2013;Pauklin and Vallier 2013), our results reveal that control of G2 exit also plays an essential role in regulating progenitor differentiation.…”

Initiation of stem cell differentiation involves cell cycle-dependent regulation of developmental genes by Cyclin D

“…The importance of these mechanisms has been demonstrated in adult stem cells (Oshimori and Fuchs 2012) and also in pluripotent stem cells (Sela et al 2012;Calder et al 2013;Coronado et al 2013;Singh et al 2013Singh et al , 2015. Human embryonic stem cells (hESCs) represent an advantageous model system for investigating the cross-talk between cell cycle and cell fate choice.…”

“…hESCs can proliferate indefinitely while maintaining the capacity to differentiate into the three primary germ layers neuroectoderm, mesoderm, and endoderm in vitro. Furthermore, hESCs are characterized by a specific cell cycle profile with a short G1 phase, while their differentiation is associated with an increase in G1 phase length (Coronado et al 2013). A recent study has shown that Cyclin D1-3/CDK4/6 complexes, which control G1 length and progression, also limit the transcriptional activity associated with Activin/Nodal signaling during the late G1 phase.…”

The matrix protein Tiggrin regulates plasmatocyte maturation in Drosophila larva

“…9). In pluripotent stem cells, cells in G 1 phase are more likely to undergo differentiation Calder et al, 2013;Coronado et al, 2013;Sela et al, 2012), possibly owing to cell cycle stagedependent expression of key developmental regulators (Pauklin and Vallier, 2013;Singh et al, 2015). Perhaps our data showing that Wee1 and Stg regulate Tig expression is an example of G 2 phasedependent developmental regulation.…”