Elucidating the role of multiple feedback loops in regulating stem cell decisions

Stem cell decisions are regulated by a complex network of gene regulatory pathways that determine the reproductive health of the tissue. The Drosophila ovarian germline is a well-characterized model system which facilitates visualizing stem cell behavior in its native environment to attain a systems-level understanding of the stem cell dynamics. The asymmetric division of the Germline Stem Cells (GSCs) forms two daughter cells-a self-renewed GSC and a differentiated Cystoblast (CB). The highly conserved Bone Morphogenetic Protein (BMP) pathway ensures growth and maintenance of the GSCs, but is downregulated in the CBs, to allow for differentiation. BMP signal transduction upregulates dad and represses Fused, both of which are negative regulators of the BMP pathway. Moreover, these regulatory mechanisms operate on a system of two cells which remain connected during a portion of the cell cycle. We developed a biologically-informed mathematical model of multi-compartment GSC division to investigate the dynamic roles Dad and Fused play in determining cell fate. We found that Dad optimally controls the BMP signal transduction to enable GSC homeostasis and differentiation. In dadKO mutants, GSCs were more likely to divide symmetrically. Our work identifies the synergistic role of Dad and Fused rendering robustness to stem cell division.