All Phenotypes Ap1m2<tm1.1Ohno> MGI Mouse

premature death ( J:226582 )

• approximately half of homozygotes die before 8 weeks of age

postnatal lethality, incomplete penetrance ( J:226582 )

• increased mortality between the neonatal period and weaning age

decreased body weight ( J:226582 )

• significantly reduced body weight in both sexes at 2-7 weeks of age

postnatal growth retardation ( J:226582 )

• surviving mice exhibit growth retardation

abnormal intestinal epithelium morphology ( J:226582 )

• impaired polarized sorting in the small intestine epithelium, as shown by the mislocalization of basolateral membrane proteins, including the low-density lipoprotein receptor (LDLR), EphB2, and E-cadherin

• the apical marker sucrase is mistargeted to the lateral plasma membrane, while both sucrase and villin (an actin-bundle protein normally anchored beneath the apical membrane) show abnormal subcellular localizations

• small vesicular structures, likely endosomes, normally found in the subapical domain and around the Golgi apparatus of control epithelial cells, are scarce; instead, enlarged lysosome-like vacuoles are observed

• partial defect in E-cadherin sorting with abnormal E-cadherin accumulation in cytoplasmic granular structures associated with an increase in the nuclear translocation of free beta-catenin in the intestinal epithelium; however, normal localization of E-cadherin in lung and kidney epithelial cells

abnormal small intestine morphology ( J:226582 )

• ~3-fold enlargement of the small intestine relative to heterozygous controls

• significantly increased small intestine weight around weaning (3-5 weeks) and at 7-10 weeks (adults) relative to heterozygous controls

abnormal small intestine crypts of Lieberkuhn morphology ( J:226582 )

• marked elongation of the duodenal crypts along with abnormally thicker and shorter villi relative to heterozygous controls

• similar pathology in the jejunum and ileum although phenotype is less severe descending along the anterior-posterior axis of the small intestine

• however, antibotics treatment fails to ameliorate crypt elongation in the upper small intestine

abnormal duodenum crypts of Lieberkuhn morphology ( J:226582 )

• significantly increased duodenum crypt length relative to controls

abnormal jejunum crypts of Lieberkuhn morphology ( J:226582 )

• significantly increased jejunum crypt length relative to controls

duodenum polyps ( J:226582 )

• multiple duodenal polyps in all mice examined at 11-13 months of age

enlarged duodenum ( J:226582 )

abnormal small intestinal villus morphology ( J:226582 )

• villous dysplasia with abnormally thicker and shorter villi in the duodenum relative to controls

• duodenal villi appear highly disorganized; the luminal surface is extremely flat and individual villi are hardly discernible by EM

abnormal small intestinal microvillus morphology ( J:226582 )

• TEM revealed sparse and disorganized apical microvilli in the small intestine epithelium, unlike the well-ordered brush-like microvilli seen in control epithelium

• ectopic formation of microvillus-like structures is observed at the lateral membrane, unlike in controls

decreased small intestinal villus height ( J:226582 )

• significantly reduced villus length in the duodenum, but not in the jejunum or ileum

abnormal intestine physiology ( J:226582 )

• dysplasia of small intestinal villi and microvilli resulting in a digestive and/or absorptive disorder that causes malnutrition

• excessive proliferation of small intestinal epithelial cells due to destabilization of the E-cadherin/beta-catenin complex at the adherens junction and nuclear translocation of beta-catenin

abnormal small intestinal crypt cell proliferation ( J:226582 )

• crypt hyperplasia due to excessive proliferation of epithelial cells, as shown by abundant Ki67+ cells throughout the elongated crypts in the upper small intestine

• blockade of Notch signaling by the gamma-secretase inhibitor dibenzazepine slightly reduces the number of Ki67+ epithelial cells but fails to ameliorate crypt elongation (hyperplasia)

• in contrast, blockade of beta-catenin signaling by IWR1 treatment significantly decreases the number of Ki67+ cells and ameliorates crypt hyperplasia

• notably, the composition of untreated epithelial cells is grossly normal in all parts of the small intestine

decreased circulating glucose level ( J:226582 )

• significant decrease in serum glucose levels at 8-10 weeks of age

increased circulating cholesterol level ( J:226582 )

• small but significant increase in total serum cholesterol levels at 8-10 weeks of age

decreased circulating serum albumin level ( J:226582 )

• significant decrease in serum albumin levels at 8-10 weeks of age