Phenotypes for Timp3 MGI:3056103 MGI Mouse

mortality/aging ( J:92948 , J:102205 )

N	• Background Sensitivity: unlike homozygotes of a mixed genetic background, homozygotes on a congenic C57BL/6 background do not succumb to morbidity through lung dysfunction (J:92948) (J:102205)

increased susceptibility to induced morbidity/mortality ( J:92948 )

• at 144 hrs after partial hepatectomy, 4 of six 9-12-wk-old homozygotes become moribund and the remaining 2 show decreased liver to body mass ratios whereas all wild-type mice appear healthy with normal liver body mass ratios

increased tumor necrosis factor secretion ( J:92948 )

• at 12 weeks, homozygotes exhibit a 1.8-fold increase in TNF converting enzyme activity (ADAM17), as well as constitutive release of TNF and activation of TNF signaling in the liver

• in hepatic sinusoids, constitutive TNF shedding is detected in Kupffer cells, the resident macrophages of the liver

liver inflammation ( J:92948 )

• aging homozygotes display progressive hepatic inflammation with periportal lymphocytic infiltrates that are neither clonogenic nor tumoral

increased hepatocyte apoptosis ( J:92948 )

• after partial hepatectomy, necrosis in regenerating livers is accompanied by increased TNF activity and hepatocyte apoptosis

• hepatocyte cell death is fully rescued by a neutralizing antibody to TNF

hepatic necrosis ( J:92948 )

• at 18-22 months, homozygotes display hepatic necrosis; however, no excessive collagen deposition or fibrosis is observed

liver inflammation ( J:92948 )

• aging homozygotes display progressive hepatic inflammation with periportal lymphocytic infiltrates that are neither clonogenic nor tumoral

abnormal liver lobule morphology ( J:92948 )

• aging homozygotes exhibit major progressive changes in periportal lobular architecture

impaired liver regeneration ( J:92948 )

• following partial hepatectomy, all 9-12 week-old homozygotes show a significant reduction in liver to body mass ratio

• failure of liver regeneration occurs despite accelerated progression of the cell cycle in mutant hepatocytes

• by 72 hours, regenerating livers of homozygotes show multiple foci of necrosis; extensive hepatocyte vacuolization is noted by 144 hours

respiratory system phenotype ( J:92948 , J:102205 )

N	• unlike the original mixed strain, C57BL/6 homozygotes do not succumb to morbidity through lung dysfunction (J:92948) (J:102205)

abnormal branching involved in terminal bronchiole morphogenesis ( J:85546 )

• as early as E12.5, homozygotes display reduced bronchiole branching relative to wild-type

• in vitro, E11.5 homozygotes possess only 62% of peripheral terminal buds found in wild-type

• gelatin and in situ zymography indicated enhanced MMP-mediated degradation of fibronectin in the basement membrane and in the stroma surrounding the developing bronchiole epithelium

impaired lung alveolus development ( J:85546 , J:161579 )

• lungs from newborn homozygotes display deficient alveolarization relative to wild-type (J:85546)

• defective alveologenesis putatively due to excessive matrix metalloproteinase (MMP) activity and inappropriate ECM degradation in the developing lung (J:161579)

abnormal pulmonary alveolus wall morphology ( J:161579 )

• at P1-P14 (early alveologenesis), mutant alveolar walls appear to be thinner than wild-type controls

• however, no significant differences in collagen content are observed during sacculation or alveologenesis, as determined by trichrome staining of alveolar walls

overexpanded pulmonary alveolus ( J:161579 )

• airspaces are already dilated at birth (P1) and continue to increase in size over the course of early alveolarization (P5-P14)

• mutant alveoli are 26% larger at P1, 27% larger at P5, 32% larger at P9, and 43% larger at P14 relative to wild-type controls

• gelatin zymography revealed a significant increase in abundance of active MMP2 in mutant lung extracts at P1 (180%) and P5 (150%) but not later

• injection of mutant pregnant dams with a synthetic metalloproteinase inhibitor (GM6001) on E16.5 results in mutant pups with a modest but significant reduction in mean alveolar size at P1 but not at P14

dilated terminal bronchiole tube ( J:85546 )

• lungs from newborn homozygotes display dilated terminal buds

abnormal heart morphology ( J:102205 )

• exhibit a significant loss of perimysial collagen fibers in hearts and a reduction in the fiber connectivity of the collagen network

cardiac hypertrophy ( J:102205 )

• heart-to-body weight ratio is higher at 21 months of age, accompanied by increased cardiomyocyte cross-sectional area indicating cardiomyocyte hypertrophy

• cardiomyocyte hypertrophy becomes evident at 16 months of age

dilated heart left ventricle ( J:102205 )

• left ventricular volume is increased at 21 months of age

dilated cardiomyopathy ( J:102205 )

• exhibit features of human dilated cardiomyopathy, including chamber dilation, cellular hypertrophy without myocardial wall thickening, and impaired contractile performance

decreased ventricle muscle contractility ( J:102205 )

• with aging, exhibit a reduction in + dP/dt and diminished fractional shortening indicating impaired ventricular contractility

abnormal cardiac muscle relaxation ( J:102205 )

• with age, exhibit a reduction in dP/dt and an increase in tau suggesting delayed ventricular relaxation

decreased left ventricle developed pressure ( J:102205 )

• with age, exhibit reduction in left ventricular developed pressure

decreased left ventricle systolic pressure ( J:102205 )

• with age, exhibit reductions in left ventricular peak systolic pressure