ADAM10 Regulates Notch Function in Intestinal Stem Cells of Mice

Tsai, Y. H., Van Dussen, K. L., Sawey, E. T., Wade, A. W., Kasper, C., Rakshit, S., Bhatt, R. G., Stoeck, A., Maillard, I., Crawford, H. C., Samuelson, L. C., Dempsey, P. J. (July 2014) ADAM10 Regulates Notch Function in Intestinal Stem Cells of Mice. Gastroenterology. ISSN 0016-5085

URL: http://www.ncbi.nlm.nih.gov/pubmed/25038433
DOI: 10.1053/j.gastro.2014.07.003

Abstract

BACKGROUND & AIMS: ADAM10 is a cell surface sheddase that regulates physiological processes including Notch signaling. ADAM10 is expressed in all intestinal epithelial cell types but the requirement for ADAM10 signaling in crypt homeostasis is not well defined. METHODS: We analyzed intestinal tissues from mice with constitutive (Vil-Cre;Adam10f/f mice) and conditional (Vil-CreER;Adam10f/f and Lgr5-CreER;Adam10f/f mice) deletion of ADAM10. We performed cell lineage tracing experiments in mice that expressed a gain-of-function allele of Notch in the intestine (Rosa26NICD) or mice with intestine-specific disruption of Notch (Rosa26DN-MAML), to examine the effects of ADAM10 deletion on cell fate specification and intestinal stem cell maintenance. RESULTS: Loss of ADAM10 from developing and adult intestine caused lethality associated with altered intestinal morphology, reduced progenitor cell proliferation, and increased secretory cell differentiation. ADAM10 deletion led to the replacement of intestinal cell progenitors with 2 distinct, post-mitotic, secretory cell lineages: intermediate-like (Paneth/goblet) and enteroendocrine cells. Based on analysis of Rosa26NICD and Rosa26DN-MAML mice, we determined that ADAM10 controls these cell fate decisions by regulating Notch signaling. Cell lineage tracing experiments showed that ADAM10 is required for survival of Lgr5+ crypt-based columnar cells. Our findings indicate that Notch-activated stem cells have a competitive advantage for occupation of the stem cell niche. CONCLUSIONS: ADAM10 acts in a cell autonomous manner within the intestinal crypt compartment to regulate Notch signaling. This process is required for progenitor cell lineage specification and crypt-based columnar cell maintenance.

Item Type: Paper
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell signaling
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells
CSHL Authors:
Communities: CSHL Press
Depositing User: Matt Covey
Date: 16 July 2014
Date Deposited: 25 Jul 2014 15:36
Last Modified: 25 Jul 2014 15:36
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30551

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