Table 2.
Effect of global and conditional Adam17 deletion on gastrointestinal tract function and pathophysiology
| ADAM17-deficient mouse models |
Tissue distribution |
Experimental model | Gastrointestinal phenotype | Reference(s) |
|---|---|---|---|---|
| Null | ||||
| TaceΔZn/ΔZn | Global | Development | Postnatal lethality dependent on genetic background. E17.5 intestine had variably blunted villi with delayed epithelial cell maturation |
51, 67 |
| Impaired development of Peyer’s patches |
76 | |||
| Hypomorphic | ||||
| Adam17Ex/Ex | Global | IEC development | Normal crypt-villus architecture, slightly heightened intestinal inflammation |
80 |
| DSS colitis | Increased susceptibility to injury, defective Stat3 signaling |
|||
| APCMin model | Decreased tumor burden | S. Schmidt &A. Chalaris, unpublished observation |
||
| Adam17wavedX/wavedX | IEC development | Normal crypt-villus architecture |
79 | |
| DSS colitis | Increased susceptibility to injury; defective AREG/EREG → EGFR signaling in nonhematopoietic cells of the GItract |
|||
| IEC specific | ||||
|
Villin-Cre; Adam17flox/flox |
All IECs at ~E15 |
IEC development | Normal crypt-villus architecture |
81, 82, 117 |
| DSS colitis | Increased susceptibility to injury |
81, 114 | ||
| Lactobacillus rhamnosus GG p40/DSS colitis |
p40-induced EGFR signaling is ADAM17 dependent |
81 | ||
| Total parenteral nutrition | Protection against mucosal atrophy as a result of ↓TNFα signaling |
82, 114, 117 | ||
|
Villin-CreER; Adam17flox/flox |
All IECs | Adult IEC homeostasis | Normal crypt-villus architecture |
114 |
| Adam17 deletion prior to DSS colitis |
Increased susceptibility to injury |
|||
| Adam17 deletion after DSS colitis |
No effect of epithelial cell restitution/regeneration |
|||
| Leukocyte specific | ||||
|
LysM-CreER; Adam17flox/flox |
Neutrophils, monocytes, macrophages |
Adult IEC homeostasis | Normal crypt-villus architecture |
P.J. Dempsey, unpublished observation |
| DSS colitis | No difference in acute intestinal injury |
|||
| Liver specific | ||||
|
Albumin-Cre; Adam17flox/flox |
Hepatocyte | LPS-induced TNFα/TNFR1 shedding |
↓TNFα and TNFR serum levels |
122 |
| Partial hepatectomy | ↓TNFα induction; ↓TNFα, TNFR, and AREG shedding in liver; no effect on liver generation |
|||
| CCl4-induced hepatotoxicity |
No effect on liver injury | |||
|
LysM-CreER; Adam17flox/flox |
Neutrophils, monocytes, macrophages |
LPS-induced TNFα/TNFR1 shedding |
↓TNFα and TNFR serum levels |
122 |
| Partial hepatectomy | ↓TNFα induction, no effect on liver regeneration |
|||
| CCl4-induced hepatotoxicity |
No effect on liver injury | |||
| Pancreas specific | ||||
|
Ptf1a-Cre; Adam17flox/flox |
All pancreatic cell lineages |
Pancreatic development | No gross pancreatic abnormalities |
141 |
| Mouse pancreatic intraepithelial neoplasia (mPanIN-KrasLSL- G12D) model |
Reduced tumorigenesis as a result of ↓ErbB ligand shedding leading to ↓EGFR/MEK signaling |
|||
| Cerulein-induced (KrasLSL-G12D) PDAC model |
Protected against metaplasia-mPanIN formation |
|||
| Cerulein-induced pancreatitis |
Protected against pancreatitis | |||
Abbreviations: DSS, dextran sodium sulfate; E, embryonic day; IEC, intestinal epithelial cell; LPS, lipopolysaccharide; mPanIN, murine pancreatic intraepithelial neoplasia; PDAC, pancreatic ductal adenocarcinoma.