Basolateral Junction Proteins Regulate Competition for the Follicle Stem Cell Niche in the Drosophila Ovary

Abstract

Epithelial stem cells are routinely lost or damaged during adult life and must therefore be replaced to maintain homeostasis. Recent studies indicate that stem cell replacement occurs through neutral competition in many types of epithelial tissues, but little is known about the factors that determine competitive outcome. The epithelial follicle stem cells (FSCs) in the Drosophila ovary are regularly lost and replaced during normal homeostasis, and we show that FSC replacement conforms to a model of neutral competition. In addition, we found that FSCs mutant for the basolateral junction genes, lethal giant larvae (lgl) or discs large (dlg), undergo a biased competition for niche occupancy characterized by increased invasion of neighboring FSCs and reduced loss. Interestingly, FSCs mutant for a third basolateral junction gene, scribble (scrib), do not exhibit biased competition, suggesting that Lgl and Dlg regulate niche competition through a Scrib-independent process. Lastly, we found that FSCs have a unique cell polarity characterized by broadly distributed adherens junctions and the lack of a mature apical domain. Collectively, these observations indicate that Lgl and Dlg promote the differentiation of FSC progeny to a state in which they are less prone to invade the neighboring niche. In addition, we demonstrate that the neutral drift model can be adapted to quantify non-neutral behavior of mutant clones.

Dynamic stem cell heterogeneity

“…Through a regulated process of spindle orientation, GSC division leads to a predominantly asymmetric fate outcome in which one daughter cell remains anchored to the hub and retains GSC identity, while another is displaced from the niche and enters into a differentiation pathway (Hardy et al, 1979). However, static lineagetracing studies and ex vivo live imaging in the Drosophila testis and ovary show that, even under normal physiological conditions, sporadic stem cell loss from the hub may be compensated for by the symmetric duplication of neighbouring stem cells, and vice versa, leading to neutral drift dynamics of the clonal population (Sheng and Matunis, 2011;Kronen et al, 2014). Whether these rare events are associated with chance loss or active displacement of 'inferior' GSCs, or whether infrequent symmetric divisions are a routine part of the normal program of homeostatic turnover remains unclear.…”

Phosphorylated Groucho delays differentiation in the follicle stem cell lineage by providing a molecular memory of EGFR signaling in the niche

“…To test whether either of these transcriptional regulators are also part of the programs that promote FSC self-renewal and occupancy of the niche, we performed an FSC competition assay (Kronen et al, 2014). This assay compares the fitness of a mutant FSC lineage to a wild-type FSC lineage in the same germarium.…”

“…Conversely, other mutations cause 'hypercompetition' in which the mutant FSC lineage expands at the expense of the wild-type lineage. The causes of hypercompetition are not fully understood but, in the FSC lineage, the phenotype is associated with mutations that delay pFC differentiation (Kronen et al, 2014).…”

“…1, or 2 labeled FSCs can be used to calculate rates of FSC turnover, as well as a competitive bias value (b) which describes the fitness of a mutant stem cell relative to a wild-type stem cell (Kronen et al, 2014). Bias values range from +100% to −100%, with positive values indicating that the mutant is hypercompetitive for the niche relative to wild type, negative values indicating that the mutant is hypocompetitive relative to wild type, and 0% indicating that mutant and wild type are equally competitive (neutral competition).…”

“…Although many types of stem cells segregate differentiation determinants on the timescale of a single cell division, there is growing evidence that the differentiation programs of epithelial stem cell lineages proceed gradually, over the course of several cell divisions (Barker, 2014;Franz and Riechmann, 2010;Jones et al, 2007;Kronen et al, 2014). Indeed, many epithelial stem cell lineages contain a transit-amplifying phase downstream from the stem cell division that is defined by incomplete differentiation.…”