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Cdk4 functions in multiple cell types to control Drosophila intestinal stem cell proliferation and differentiation


Adlesic, Mojca; Frei, Christian; Frew, Ian J (2016). Cdk4 functions in multiple cell types to control Drosophila intestinal stem cell proliferation and differentiation. Biology Open, 5(3):237-251.

Abstract

The proliferation of intestinal stem cells (ISCs) and differentiation of enteroblasts to form mature enteroendocrine cells and enterocytes in the Drosophila intestinal epithelium must be tightly regulated to maintain homeostasis. We show that genetic modulation of CyclinD/ Cdk4 activity or mTOR-dependent signalling cell-autonomously regulates enterocyte growth, which influences ISC proliferation and enteroblast differentiation. Increased enterocyte growth results in higher numbers of ISCs and defective enterocyte growth reduces ISC abundance and proliferation in the midgut. Adult midguts deficient for Cdk4 show severe disruption of intestinal homeostasis characterised by decreased ISC self-renewal, enteroblast differentiation defects and low enteroendocrine cell and enterocyte numbers. The ISC/ enteroblast phenotypes result from a combination of cell autonomous and non-autonomous requirements for Cdk4 function. One nonautonomous consequence of Cdk4-dependent deficient enterocyte growth is high expression of Delta in ISCs and Delta retention in enteroblasts.We postulate that aberrant activation of the Delta–Notch pathway is a possible partial cause of lost ISC stemness. These results support the idea that enterocytes contribute to a putative stem cell niche that maintains intestinal homeostasis in the Drosophila anterior midgut.

Abstract

The proliferation of intestinal stem cells (ISCs) and differentiation of enteroblasts to form mature enteroendocrine cells and enterocytes in the Drosophila intestinal epithelium must be tightly regulated to maintain homeostasis. We show that genetic modulation of CyclinD/ Cdk4 activity or mTOR-dependent signalling cell-autonomously regulates enterocyte growth, which influences ISC proliferation and enteroblast differentiation. Increased enterocyte growth results in higher numbers of ISCs and defective enterocyte growth reduces ISC abundance and proliferation in the midgut. Adult midguts deficient for Cdk4 show severe disruption of intestinal homeostasis characterised by decreased ISC self-renewal, enteroblast differentiation defects and low enteroendocrine cell and enterocyte numbers. The ISC/ enteroblast phenotypes result from a combination of cell autonomous and non-autonomous requirements for Cdk4 function. One nonautonomous consequence of Cdk4-dependent deficient enterocyte growth is high expression of Delta in ISCs and Delta retention in enteroblasts.We postulate that aberrant activation of the Delta–Notch pathway is a possible partial cause of lost ISC stemness. These results support the idea that enterocytes contribute to a putative stem cell niche that maintains intestinal homeostasis in the Drosophila anterior midgut.

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Contributors:C. Lehner and K. Basler (University of Zü rich), H. Stocker and E. Hafen (ETH, Zü rich), W. Krek (ETH, Zü rich), N. Buchon (EPFL, Lausanne) and S. Bray (University of Cambridge) for fly stocks and reagents, E. Hafen (ETH Zurich) and D. Bopp (University of Zürich) for providing lab space and equipment., Microscopy was conducted using the facilities of the Centre for Microscopy and Image Analysis (University of Zurich)
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2016
Deposited On:01 Sep 2016 14:59
Last Modified:08 Dec 2017 20:18
Publisher:The Company of Biologists Ltd.
ISSN:2046-6390
Funders:Swiss National Science Foundation professorships to C.F. [PP00A-106737] and I.J.F. [PP00P3-150755]
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1241/BIO.016584
PubMed ID:26879465

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