Reviewer #1's Review; (José-Eduardo Gomes, Ecole Normale Supérieure, Paris)

“In the C. elegans somatic gonad lineage the Z1aa and Z4pp cells differentiate into distal tip cells (DTCs) while their sister cells, Z1ap and Z4pa respectively, remain quiescent until a much later stage of development. Thorough a series of laser ablation experiments the authors show that in cye-1 mutants Z1ap/Z4pa differentiate into DTCs, like their sister-cells do. No other cells in the lineage show this behavior in cye-1 mutants. The authors show, although in a less detailed analysis that cdk-2 loss of function causes the same phenotypes, consistent with the expectation for these two molecules to act together. Using a CYE-1::GFP transgene that rescues the cye-1 mutant phenotype the authors report a protein localization consistent with the mutant phenotype described, CYE-1::GFP is strongly expressed in Z1ap/Z4pa and weakly in Z1aa/Z4pp, furthermore this asymmetry of CYE-1::GFP levels between sister cells is dependent on the Wnt/MAPK pathway.
Moreover the authors show that upon RNAi against cki-1 (CKI) there are extra cell divisions in Z1a and Z4p lineaeges, a phenotype somewhat opposite to cye-1/cdk-2 mutants. furthermore cye-1/cdk-2 are epistatic to cki-1 for this phenotype. One important. Finally the authors present preliminary evidence that cye-1 may have a similar role in other cell lineages, namely in the hypodermis.

The authors propose cye-1/cdk-2 (Cyclin E/CDK2) have a role in promoting quiescence of Z1ap/Z4pa and repressing terminal differentiation. This role is independent of their canonical function in promoting transition from G1 to S phase of the cell cycle. In the proposed model cki-1 (CKI), would be a repressor of cye-1/cdk-2, and the decision of differentiation vs quiescence would be regulated by the relative levels of cye-1/cdk-2 and cki-1. Although the molecular mechanism for the cell cycle independent role of cye-1/cdk-2 remains elusive, this model is consistent with the observations presented. The authors present a good discussion of their results in view of the previously published literature on this topic. This findings are of interest to researchers working on cell cycle, but mostly to those interested in the link between cell cycle regulation and developmental, as it provides insight in how one cyclin may be involved in regulation of differentiation and fate acquisition
Understanding the molecular basis of the cell cycle independent function if cye-1/cdk-2 seems to me the most interest question for further research.”

N.B. These are the general comments made by the reviewer when reviewing this paper. Specific points addressed during revision of the paper are not shown.