Abstract
Precise regulation of stem cell self-renewal and differentiation properties is essential for tissue homeostasis. Using the adult Drosophila intestine to study molecular mechanisms controlling stem cell properties, we identify the gene split-ends (spen) in a genetic screen as a novel regulator of intestinal stem cell fate (ISC). Spen family genes encode conserved RNA recognition motif-containing proteins that are reported to have roles in RNA splicing and transcriptional regulation. We demonstrate that spen acts at multiple points in the ISC lineage with an ISC-intrinsic function in controlling early commitment events of the stem cells and functions in terminally differentiated cells to further limit the proliferation of ISCs. Using two-color cell sorting of stem cells and their daughters, we characterize spen-dependent changes in RNA abundance and exon usage and find potential key regulators downstream of spen. Our work identifies spen as an important regulator of adult stem cells in the Drosophila intestine, provides new insight to Spen-family protein functions, and may also shed light on Spen’s mode of action in other developmental contexts.
Highlights
During development, pluripotent stem cells will give rise to all of the different cell types present in the organism
Our findings suggest that spen acts at an early step in stem cell commitment limiting stem cell fate acquisition and further controls stem cell proliferation non-autonomously in terminally differentiated cells
By assessing the effects of spen on RNA transcript levels and exon usage, we find that Spen controls a number of genes encoding proteins with similar functions, some of which may explain previously described roles of spen during development
Summary
Pluripotent stem cells will give rise to all of the different cell types present in the organism. Adult stem cells have more limited plasticity and play essential roles in tissue homeostasis and regeneration by both renewing the differentiated cells as well as maintaining the stem cell pool. Defining the mechanisms governing stem cell self-renewal and differentiation is essential for understanding both organism development as well as tissue maintenance and regeneration. The fly intestine is renewed by intestinal stem cells (ISCs), which produce progenitor cells that differentiate into terminally differentiated polyploid absorptive enterocytes (ECs) and diploid secretory enteroendocrine cells (EEs) [2, 3] (Fig 1A). Delta-Notch signaling between stem cell daughters results in Notch activation in EB progenitors that will further promote differentiation into EC cells, whereas inhibition of Notch by Numb and expression of Scute promotes EE fate acquisition [4, 25, 27]. Outside of canonical Notch signaling components, little is known about the mechanisms controlling ISC fate acquisition leading to robust asymmetric fate acquisition after ISC division
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