title: ADAM10 regulates Notch function in intestinal stem cells of mice.
abstract: OBJECTIVE
  A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is a cell surface sheddase that regulates physiologic 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;Adam10(f/f) mice) and conditional (Vil-CreER;Adam10(f/f) and Leucine-rich repeat-containing GPCR5 [Lgr5]-CreER;Adam10(f/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 (Rosa26(NICD)), or mice with intestine-specific disruption of Notch (Rosa26(DN-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 Rosa26(NICD) and Rosa26(DN-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.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.
authors.forename: Yu-Hwai
authors.initials: YH
authors.lastname: Tsai
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: VanDussen
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Sawey
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.
authors.forename: Alex W
authors.initials: AW
authors.lastname: Wade
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Kasper
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.
authors.forename: Sabita
authors.initials: S
authors.lastname: Rakshit
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.
authors.forename: Riha G
authors.initials: RG
authors.lastname: Bhatt
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.
authors.forename: Alex
authors.initials: A
authors.lastname: Stoeck
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Crawford
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Samuelson
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan. Electronic address: peter.dempsey@ucdenver.edu.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dempsey
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D049109:Cell Proliferation; D002470:Cell Survival; D019858:Enteroendocrine Cells / Q000201:enzymology; D020397:Goblet Cells / Q000201:enzymology; D007422:Intestines / Q000166:cytology / Q000201:enzymology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009940:Organoids; D019879:Paneth Cells / Q000201:enzymology; D010641:Phenotype; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D055153:Stem Cell Niche; D013234:Stem Cells / Q000201:enzymology*; D013997:Time Factors
chemical_list: D008565:Membrane Proteins; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse
keywords: CBC; Development; Differentiation; Intestinal Epithelium