Nitsure, N. | Search bioRxiv

bioRxiv2020

Cell cycle lengths of stem cells and their lineage from cellular demography

Adult stem cells and their transit-amplifying (TA) progeny dynamically alter their proliferation rates to maintain tissue homeostasis. To test how the division rates of stem cell and TA cells affect tissue growth and differentiation, we developed a computation strategy which estimates the average cell cycle lengths/lifespans of germline stem cells (GSCs) and their TA progeny from cellular demography. Analysis of the wild-type data from Drosophila testis using this method indicated anomalous changes in lifespans during the germline transit-amplification with a nearly 1.3-fold increase after the first division and about a 2-fold decrease in the subsequent stage. Genetic perturbations altering the cell cycle rates of GSC and its immediate daughter, the gonialblast (GB), proportionately changed the rates of subsequent TA divisions. Notably, a nearly 2-fold increase or decrease in the total TA duration did not alter the induction of meiosis after four mitotic cycles. Altogether, these results suggest that the rates of GSC and GB divisions can adjust the rates of subsequent divisions and the onset of differentiation. Significance StatementDynamic regulation of the proliferation rate of stem cells and their transit-amplifying daughters maintains tissue homeostasis in different conditions such as tissue regeneration, aging, and hormonal imbalance. Previous studies suggested that a molecular clock in the stem cell progeny determines the timing of differentiation. This work shows that alterations of the rates of stem cell divisions, as well as that of its progeny, could override the differentiation clock in the Drosophila testis, and highlights a possible mechanism of fine-tuning the transit-amplification program under different conditions such as tissue damage, aging, and hormonal inputs. Also, the method developed for this study could be adapted to estimate lineage expansion plasticity from demographic changes in other systems. HighlightsO_LIDetermination of cellular lifespan during transit-amplification from demography C_LIO_LILifespans of Drosophila male germline cells changes anomalously during the TA C_LIO_LILifespan changes of germline stem cells readjust that of the progeny cells C_LIO_LIAnomalous lifespan expansion midway through TA precedes the Bam onset C_LI

developmental biology↗

bioRxiv2019

Cdk1 in germline and the dose of somatic EGFR signaling determine the rate of transit amplification

The division rates of stem cells and their progeny shape the growth and maintenance of tissues. Here, we present a mathematical model that could estimate the stage-wise lifespans of germline stem cells (GSCs) and subsequent transit amplifying (TA) cells from their steady-state distribution in Drosophila testis. Analysis of the wild-type data using this model indicated that the inter-division lifespans of the first two TA cycles remain similar to that of the GSCs, and then reduce by nearly 2-folds for the third and fourth cycles. Also, loss of Cyclin E and Cdk1 functions in the early germline cells, which decreased the rates of GSC divisions, is suggested to extend the lifespans of GSCs and the TA stages without affecting subsequent differentiation. Similar perturbations at the 4 and 8-cell stages, however, arrested the mitoses at the 8-cell stage, and only the Cyclin E-deficient cells continued with premature meiosis. Together, these results suggest that regulation of the G1-S and G2-M transitions in the GSCs and the rapidly dividing TA stages differentially impacts the amplification of the germline pool and subsequent differentiation. The model also helped to quantify distinct influences of these cell cycle regulatory molecules in determining the lifespans at different TA stages.\n\nHighlightsA model for calculating the lifespans of transit amplifying stages from demography. Transit-amplifying divisions accelerate by nearly 2-folds after the second mitosis. Cyclin E and Cdk1 regulate the lifespans of GSCs and transit amplifying cells. The premature arrest of the final transit amplifying division induces meiosis.

developmental biology↗