Mouse Genome Informatics
hm1
    Atg5tm1Myok/Atg5tm1Myok
involves: 129S/SvEv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
normal phenotype
• mice are normal


Mouse Genome Informatics
cn2
    Atg5tm1Myok/Atg5tm1Myok
Myl2tm1(cre)Krc/Myl2+

involves: 129S/SvEv * 129S4/SvJae
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice die after thoracic transverse aortic constriction of heart failure

cardiovascular system
• 1 week following thoracic transverse aortic constriction (TAC) or a 7 day treatment with isoproterenol left ventricular dilation is observed
• thoracic transverse aortic constriction (TAC) and isoproterenol induce severe cardiac dysfunction
• 4 weeks following TAC

homeostasis/metabolism
• following a 7 day treatment with isoproterenol the left ventricle is dilated and mice exhibit severe cardiac dysfuction, unlike wild-type mice where the treatment has no significant effect


Mouse Genome Informatics
cn3
    Atg5tm1Myok/Atg5tm1Myok
Tg(CAG-cre)13Miya/?

involves: 129S/SvEv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
liver/biliary system
• diffuse cytoplasmic signals and inclusions are found in the liver


Mouse Genome Informatics
cn4
    Atg5tm1Myok/Atg5tm1Myok
Tg(Mx1-cre)1Cgn/?

involves: 129S/SvEv * C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
liver/biliary system
• few inclusions form immediately following injection of inosinic acid-polycytidylic acid (pIpC) but large ubiquitin-positive inclusions are present 16 days post-injection


Mouse Genome Informatics
cn5
    Atg5tm1Myok/Atg5tm1Myok
Tg(Kap-cre)1Isa/0

involves: 129S/SvEv * C57BL/6 * DBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
renal/urinary system
• increased excretion of most amino acids, with significant increases in threonine, tryptophan, valine, and alanine excretion is observed in 6-month old mice
• mice exhibit mild glycosuria at 6 months of age
• at 8 weeks of age, (left) kidney weight-to-body weight is slight increased relative to littermate controls
• at 8 weeks, slight tubular cell hypertrophy is observed but interstitial nephritis or fibrosis is not apparent; accumulation of numerous crescent membranous structures in tubular epithelial cells, primarily adjacent to mitochondria is present at 6 weeks with accumulation of similar (smaller) structures observed at 9 months
• deformed mitochondria are found in tubular cells of mutants but not in controls
• accumulation of cytosolic amorphous substrates in proximal tubular cells is apparent at 6 months
• massive accumulation of p62- and ubiquitin-positive inclusion bodies is observed almost exclusively in proximal tubules at 9 months

mortality/aging
N
• all mice survive during observational period (<9 months) (J:179961)

homeostasis/metabolism
N
• no albuminuria or increased blood urea nitrogen level is observed in mice up to 9 months of age compared to littermate controls (J:179961)
• no phosphaturia is observed (J:179961)
• increased excretion of most amino acids, with significant increases in threonine, tryptophan, valine, and alanine excretion is observed in 6-month old mice
• mice exhibit mild glycosuria at 6 months of age

cellular
• in kidney cortex homogenates from 8-week old mice, conversion of microtubule-associated protein 1 light chain 3 (LC3-I) to LC3-II is suppressed, indicative of defective autophagy
• after ischemia-reperfusion injury, severely injured tubules with accumulation of tubular sediments and vacuolation in the cortex are observed, whereas injury severity is reduced in injured controls; conversion of LC-I to LC-II in cortex as measured by Western blot is significantly suppressed indicating autophagy deficiency


Mouse Genome Informatics
cn6
    Atg5tm1Myok/Atg5tm1Myok
Tg(CAG-EGFP/Map1lc3b)53Nmz/0
Tg(Cryaa-cre)10Mlr/0

involves: 129S/SvEv * C57BL/6 * DBA/2 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
vision/eye
• absent autophagy in lens fiber cells
• disorganized in the cortical region of aged mice
• however, organelle degradation is normal
• by 6 to 9 months that develops progressively with age
• severe, bilateral at 21 months
• with accumulation of insoluble oxidized proteins and crystallins

cellular
• absent in lens fiber cells


Mouse Genome Informatics
cn7
    Atg5tm1Myok/Atg5tm1Myok
Tg(Myh6-cre)2182Mds/?

involves: 129S/SvEv * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
normal phenotype
• mice are normal


Mouse Genome Informatics
cn8
    Atg5tm1Myok/Atg5tm1Myok
Tg(Nes-cre)1Kln/?

involves: 129S/SvEv * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• some mice die after 3 weeks

nervous system
• ubiquitin-positive inclusions are found in the thalamus pon, medulla, dorsal root ganglion, midbrain, cerebral cortex, hippocampus (especially in CA3 and CA4), striatum and olfactory bulb autophagosomes formation in the brain is impaired
• axonal swelling in the posterior thalamic nucleus
• loss of pyramidal cells in the cerebral cortex
• apoptosis is detected in granular cells
• axonal swelling in the cerebral cortex, nucleus gracilis, posterior thalamic nucleus, hippocampus, inferior colliculus, tricaudal pons and reticular nucleus
• however, few degenerating Purkinje cells exhibit inclusions
• ubiquitin-positive inclusions are found in the thalamus pon, medulla, dorsal root ganglion, midbrain, cerebral cortex, hippocampus (especially in CA3 and CA4), striatum and olfactory bulb
• inclusions are time-dependent and are more limited in newborns than in adults

behavior/neurological
• progressive motor and behavioral deficits after three weeks of age
• progressive motor deficits after three weeks of age including ataxia and a decrease in mean stride length
• when suspended by their tails
• at 12 weeks
• coordination, balance and grip strength are impaired in a rotarod and wire hang task
• grip strength is impaired in a rotarod and wire hang task

cellular
• autophagosomes formation in the brain is impaired

growth/size
• body weight is about 1.5-times lower than that of wild-type


Mouse Genome Informatics
cn9
    Atg5tm1Myok/Atg5tm1Myok
Tg(Vil-cre)997Gum/0

involves: 129S/SvEv * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
digestive/alimentary system
• aberrant, disorganized granules as well as decreased granule numbers are observed in these mice
• virtually all Paneth cells have lysozyme localized throughout the cell instead of being discretely packaged within vesicles
• Paneth cells also have degenerating mitochondria, loss of granules and the frequent absence of apical microvilli
• adjacent crypt lumen often contains intact Paneth granules and cytoplasm, which is a phenomenon not observed in wild-type controls

cellular
• autophagy by the ileal epithelium is severely reduced in these mice

endocrine/exocrine glands
• aberrant, disorganized granules as well as decreased granule numbers are observed in these mice
• virtually all Paneth cells have lysozyme localized throughout the cell instead of being discretely packaged within vesicles
• Paneth cells also have degenerating mitochondria, loss of granules and the frequent absence of apical microvilli
• adjacent crypt lumen often contains intact Paneth granules and cytoplasm, which is a phenomenon not observed in wild-type controls


Mouse Genome Informatics
cn10
    Atg5tm1Myok/Atg5tm1Myok
Tg(BEST1-cre)1Taf/0

involves: 129S/SvEv * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
vision/eye
N
• at 12 weeks of age, ERG responses are not different from wild-type littermate controls (J:200084)
• no significant loss of nuclei in the outer nuclear layer by 24 weeks through 1.5 years of age (J:200084)
• when control and mutant mice received an i.p. injection of 9-cis retinal and then were dark-adapted for 24 hours, scotopic and photopic electroretinogram recordings showed no significant differences in rod and cone function (J:200084)
• rod responses to bright-light stimuli are decreased at 16 weeks compared to controls
• cone responses to bright-light stimuli are decreased at 16 weeks compared to controls

cellular
• in retina pigmented epithelium (RPE) cells of mutants, degenerating phagosomes with undigested photoreceptor outer segment (POS) material are observed in contrast to controls where POS are in single-membrane phagosomes


Mouse Genome Informatics
cn11
    Atg5tm1Myok/Atg5tm1Myok
Rhebtm1.1Otsu/Rhebtm1.1Otsu
Tg(Myh6-cre)2182Mds/0

involves: 129S/SvEv * C57BL/6J * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice die around P10


Mouse Genome Informatics
cn12
    Atg5tm1Myok/Atg5tm1Myok
Tg(Myh6-cre/Esr1*)1Jmk/?

involves: 129S/SvEv * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• cardiomyocyte fiber cross-sectional area is increased following tamoxifen treatment
• however, cardiomyocyte fibers are otherwise normal
• increase in the heart to body weight ratio following tamoxifen treatment
• following tamoxifen treatment
• following tamoxifen treatment
• calcium cycling is impaired following tamoxifen treatment
• decrease in the autophagy levels following tamoxifen treatment

respiratory system
• increase in the lung to body weight ratio following tamoxifen treatment

muscle
• cardiomyocyte fiber cross-sectional area is increased following tamoxifen treatment
• however, cardiomyocyte fibers are otherwise normal
• following tamoxifen treatment