Project Summary/Abstract
The equilibrium between stem cell self-renewal and differentiation is a cornerstone of tissue health. Stem cells
must maintain healthy, heterogeneous stem cell pools throughout the lifetime of the animal, while also producing
the differentiated daughter cells necessary for optimal tissue function. Controlled shifts mediated by changes in
the specific signals that promote self-renewal versus differentiation may be leveraged for tissue repair after injury
or prevention of aging symptoms. In contrast, continuous imbalance can lead to aberrant states such as tumor
formation when self-renewal is favored, or stem cell loss when differentiation is the primary outcome. Defining
the molecular mechanisms that determine stem cell fate is therefore a pressing need.
Here, we investigate the possibility that epithelial Follicle Stem Cells (FSCs) in the fly ovary utilize classical
neurotransmitter signaling to dictate self-renewal versus differentiation fate decisions. In recent work, we
demonstrated that axon-like projections extend from FSCs in response to feeding, forming interactive webs that
span the niche. Disruption of projection growth and interactions via mutation of the axon regulators still life (sif,
TIAM-1), and sickie (NAV2) leads to developmental defects and, importantly, disrupts the balance of cell fate
markers that instruct self-renewal or differentiation. Projection growth depends on Hedgehog (Hh) signaling, with
the transcriptional activator Cubuitus Interruptus (Ci) necessary for extension. Reasoning that Ci transcriptional
targets might thus be critical for mediating communication between FSC projections and their targets (other
FSCs or germ cells), we defined the gene expression changes that occur in FSCs at 3 hours timepoints after
feeding. The proposed work focused on a highly enriched set of genes with known functions at neuromuscular
junction synapses, and the model that FSC fate is determined by the balance of GABA versus glutamate
signaling. The idea that non-neuronal stem cells communicate via neurotransmitter signaling may be applicable
to other stem cell systems, emphasizing that our precise molecular dissection of the spatio-temporal function of
candidate regulators may uncover a new fundamental mechanism for regulation of stem cell fate.