cellular phenotype

• increased cell proliferation
  • foci of duct proliferation are present in mice after 14 days of doxycycline treatment and become more prominent with continued treatment
  (MGI Ref ID J:101742)

homeostasis/metabolism phenotype

• increased circulating glucose level
  • with doxycycline treatment for 21 day, adult rescue mice show a 4-fold increase in fasting blood glucose to diabetic levels
  (MGI Ref ID J:79206)

• impaired glucose tolerance
  • when adult mice are treated with doxycycline for 0, 7, 14, or 21 days, mice show an increased early glucose response within 7 days of start of treatment and ability to recover from glucose challenge is impaired compared to untreated transgenics where glucose levels recover to basal levels within 3 hours; by 14 days of doxycycline treatment, mice have diabetes
  (MGI Ref ID J:101742)
  • adult transgenic rescue animals treated with doxycycline for 14 days exhibit a defective response to glucose challenge compared to wild-type, non mutant transgenic, or untreated rescue mice
  (MGI Ref ID J:79206)
  • cose levels recover to basal levels within 3 hours; by 14 days of doxycycline treatment, mice have diabetes
  (MGI Ref ID J:101742)

• decreased circulating glucose level
  • 14 days after doxycycline withdrawal after 14 days of treatment resulted in a significant decrease in blood glucose levels with 4/5 mice becoming normoglycemic by 28 days
  (MGI Ref ID J:101742)

• decreased insulin secretion
  • there is a marked reduction in insulin in pancreata of doxycycline-treated mice; after withdrawal of doxycycline, insulin +ve cells are detected in islets of smaller islet-like cell clusters
  (MGI Ref ID J:101742)

• increased glucagon secretion
  • in doxycycline-treated mice there is an increase in glucagons-positive cells
  (MGI Ref ID J:101742)

endocrine/exocrine gland phenotype

• abnormal pancreatic beta cell morphology
  • after 14 or 28 days of dox treatment there are, still present, beta cells which lack insulin
  (MGI Ref ID J:101742)

• abnormal pancreas development
  • d with no acinar or islet tissue
  (MGI Ref ID J:79206)
  • pancreas of transgenic rescue newborn mice is 50% the size of a normal wild-type neonatal pancreas
  (MGI Ref ID J:79206)
  • treatment of pregnant mice with doxycycline from the first day of pregnancy through parturition prevents formation of the pancreas in mice with the transgenic rescue genotype
  (MGI Ref ID J:79206)
  • treatment on E11.5 arrests pancreatic development ~36 hours later; at birth the underdeveloped remnant consisted of a large and extended duct with several terminal, aborted, ductal buds with ducts lined with a single layer of primitive epithelial cells and with no acinar or islet tissue
  (MGI Ref ID J:79206)

• increased glucagon secretion
  • in doxycycline-treated mice there is an increase in glucagons-positive cells
  (MGI Ref ID J:101742)

• small pancreatic islets
  • after dox treatment for 14 days, there is a significant decrease in islet area compared to wild-type
  (MGI Ref ID J:101742)

• decreased insulin secretion
  • there is a marked reduction in insulin in pancreata of doxycycline-treated mice; after withdrawal of doxycycline, insulin +ve cells are detected in islets of smaller islet-like cell clusters
  (MGI Ref ID J:101742)

mammalian phenotype

• liver/biliary system phenotype
  • Normal - mice exhibit normal development of the gall bladder, collecting ducts, and common duct
  (MGI Ref ID J:151981)

homeostasis/metabolism phenotype

• impaired glucose tolerance
  • heterozygotes display partially impaired glucose tolerance compared to wild-type mice; doxycycline treatment has no effect
  (MGI Ref ID J:79206)
  • heterozygotes display partially impaired early response to glucose challenge compared to wild-type mice; ability to recover after glucose challenge is impaired
  (MGI Ref ID J:101742)

endocrine/exocrine gland phenotype

• abnormal pancreas development
  • with treatment from E12.5, pancreatic dorsal and ventral remnants composed of convoluted partially branched duct-like epithelium of columnar epithelium are present, and show a block at the stage of acinar cell formation
  (MGI Ref ID J:103522)
  • treatment from E11.5 allows the formation of a larger crude duct-like structure with a few distal primary branches; treatement from E12.5 permits formation of extensive fine structure consisting of immature acini and associated small ductules
  (MGI Ref ID J:103522)
  • examination of embryo ductal remnants from mice treated with dox from E11.5 show an absence of preacini; treatment from E12.5 results in a larger remnant with a smaller proportion of primitive duct; the epithelium is replaced by numerous eosinophilic clusters lacking ductal markers which are polarized, arranged around a central lumen and resemble immature acini
  (MGI Ref ID J:103522)
  • doxycycline from E9.5 diminishes epithelial morphogenesis; treatement from E9.5 allows outgrowth of a linear epithelial tube with nascent invaginations representing initial primary branching
  (MGI Ref ID J:103522)
  • ters lacking ductal markers which are polarized, arranged around a central lumen and resemble immature acini
  (MGI Ref ID J:103522)
  • when dams are treated with doxycycline from conception through birth, only small epithelial remnants of the pancreas form; treatment at E7.5 or E8.5 results in the same phenotype
  (MGI Ref ID J:103522)

• absent pancreas
  • ~1/5 pups are born without a pancreas; rescue of pancreas formation is observed in ~80% of transgenic mice
  (MGI Ref ID J:103522)

homeostasis/metabolism phenotype

• impaired glucose tolerance
  • transgenic mice gradually attain an impaired glucose tolerance response to glucose challenge
  (MGI Ref ID J:103522)