Abstract
The Drosophila adult midgut contains intestinal stem cells that support homeostasis and repair. We show here that the leucine zipper protein Bunched and the adaptor protein Madm are novel regulators of intestinal stem cells. MARCM mutant clonal analysis and cell type specific RNAi revealed that Bunched and Madm were required within intestinal stem cells for proliferation. Transgenic expression of a tagged Bunched showed a cytoplasmic localization in midgut precursors, and the addition of a nuclear localization signal to Bunched reduced its function to cooperate with Madm to increase intestinal stem cell proliferation. Furthermore, the elevated cell growth and 4EBP phosphorylation phenotypes induced by loss of Tuberous Sclerosis Complex or overexpression of Rheb were suppressed by the loss of Bunched or Madm. Therefore, while the mammalian homolog of Bunched, TSC-22, is able to regulate transcription and suppress cancer cell proliferation, our data suggest the model that Bunched and Madm functionally interact with the TOR pathway in the cytoplasm to regulate the growth and subsequent division of intestinal stem cells.Electronic supplementary materialThe online version of this article (doi:10.1007/s12015-015-9617-5) contains supplementary material, which is available to authorized users.
Highlights
Homeostasis and regeneration of an adult tissue is normally supported by resident stem cells
We show that Bun and myeloid leukemia factor adaptor molecule (Madm) are intrinsically required for intestinal stem cell (ISC) growth and division
Bun physically and functionally interacts with Madm, which has been proposed as a cytoplasmic adaptor protein [36]
Summary
Homeostasis and regeneration of an adult tissue is normally supported by resident stem cells. The intestine with fast cell turnover rate supported by actively proliferating stem cells is a robust system to study tissue homeostasis [2]. Two inter-converting intestinal stem cell (ISC) populations marked by Bmi and Lgr located near the crypt base can replenish cells of various lineages along the crypt-villus axis [3,4,5]. Recent data suggest that Lgr5+ cells are the main stem cell population and that immediate progeny destined for the secretory lineage can revert to Lgr5+ stem cells under certain conditions [6, 7]. The results suggest previously unexpected plasticity in stem cell maintenance and differentiation in the adult mammalian intestine
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