behavior/neurological phenotype

• hypoactivity
  • older (6-8 months) fifth generation mutants often show a sudden decrease in activity
  (MGI Ref ID J:110900)

cardiovascular system phenotype

• abnormal angiogenesis
  • large abnormal vessels are present in the induced tumors of fifth generation mutants
  (MGI Ref ID J:74001)
  • late generation mutants show decreased angiogenic potential in a basement membrane matrix assay
  (MGI Ref ID J:74001)
  • microvessel density is decreased in the induced tumors of fifth generation mutants
  (MGI Ref ID J:74001)

• abnormal cardiac muscle contractility
  • fifth generation, but not second generation, mutants exhibit a decrease in +dP/dt
  (MGI Ref ID J:110900)

• abnormal cardiac muscle relaxation
  • fifth generation mutants exhibit a decrease in -dP/dt
  (MGI Ref ID J:110900)

• abnormal cardiovascular system physiology
  • fifth generation, but not second generation, mutants suffer from a severe left ventricular failure
  (MGI Ref ID J:110900)

• abnormal fetal cardiomyocyte proliferation
  • second and fifth generation mutants exhibit decreased cardiac myocyte proliferation
  (MGI Ref ID J:110900)

• abnormal myocardial fiber morphology
  • the volume of binucleated cardiomyocytes is increased by 24% in second generation mutants and 52% in fifth generation mutants
  (MGI Ref ID J:110900)
  • the volume of mononucleated cardiomyocytes is increased by 39% and 43% in second and fifth generation mutants, respectively
  (MGI Ref ID J:110900)

• cardiac hypertrophy
  • fifth generation mutants exhibit cardiac myocyte hypertrophy
  (MGI Ref ID J:110900)

• congestive heart failure
  • older fifth generation mutants die of heart failure
  (MGI Ref ID J:110900)

• decreased heart left ventricle weight
  • left ventricle weight is decreased in fifth generation mutants
  (MGI Ref ID J:110900)

• decreased heart weight
  • heart weight is decreased in fifth generation mutants
  (MGI Ref ID J:110900)

• decreased left ventricle developed pressure
  • fifth generation mutants exhibit a decrease in LV developed pressure
  (MGI Ref ID J:110900)

• decreased myocardial fiber number
  • cardiomyocyte number is decreased 16% and 49% in second and fifth generation mutants, respectively
  (MGI Ref ID J:110900)

• dilated cardiomyopathy
  • dilated cardiomyopathy develops in fifth generation mutants
  (MGI Ref ID J:110900)

• heart left ventricle hypertrophy
  • fifth generation mutants show a reduction in left ventricle mass that is accompanied by a decrease in left ventricle mass:chamber volume ratio, indicating decompensated eccentric left ventricle hypertrophy in the absence of an absolute increase in ventricular weight
  (MGI Ref ID J:110900)
  • ular weight
  (MGI Ref ID J:110900)

• increased cardiomyocyte apoptosis
  • fifth generation mutants exhibit a 63% increase in cardiomyocyte apoptosis
  (MGI Ref ID J:110900)

• increased left ventricle diastolic pressure
  • fifth generation mutants exhibit an elevation of LV end-diastolic pressure
  (MGI Ref ID J:110900)

cellular phenotype

• abnormal chromosome morphology
  • lack of perinuclear distribution of telomeres in fourth generation mutants
  (MGI Ref ID J:89751)

• abnormal fetal cardiomyocyte proliferation
  • second and fifth generation mutants exhibit decreased cardiac myocyte proliferation
  (MGI Ref ID J:110900)

• abnormal male germ cell apoptosis
  • apoptotic depletion of germ cells in late generation mutants
  (MGI Ref ID J:120065)
  • in response to telomere shortening, male germ cells undergo apoptosis
  (MGI Ref ID J:89751)

• abnormal oocyte morphology
  • the number of oocytes that form synaptonemal complexes is decreased
  (MGI Ref ID J:89751)

• abnormal spermatocyte morphology
  • apoptosis is increased 5-fold in seminiferous tubules of G4 homozygotes; apoptosis is found in the outer layers of spermatocytes whereas the inner layer of spermatogonia remains intact
  (MGI Ref ID J:89751)

• abnormal telomere length
  (MGI Ref ID J:74001)
  • cardiac myocytes of second and fifth generation mutants show telomere shortening, with cardiomyocytes from older mutants having shorter telomeres than in younger mutants
  (MGI Ref ID J:110900)
  • cells from embryos that fail to close the neural tube have shorter telomeres and decreased viability than mutants with a closed neural tube
  (MGI Ref ID J:53600)
  • embryonic fibroblast cells derived from mutant mice after the fourth generation lacked detectable telomeric repeats and were often aneupolid with chromosomal abnormalities, including end to end fusions
  (MGI Ref ID J:43517)
  • keratinocytes exhibit a significant decrease in average telomere length compared with wild-type cells
  (MGI Ref ID J:96945)
  • splenocytes from non-immunized fifth generation mutants contain shorter telomere lengths than wild-type
  (MGI Ref ID J:60223)
  • telomere shortening occurs in both meiocytes with normal and abnormal synapsis
  (MGI Ref ID J:89751)
  • the anaphase bridge index (ABI) is increased in late-generation (G4/G5) intestinal crypts indicating telomere dysfunction
  (MGI Ref ID J:120065)
  • upon immunization with an antigen, proliferating splenocyte telomeres are shortened during germinal center formation, unlike in wildtype mice which show elongation of telomeres, however telomeres are longer than seen in non-immunized mutants
  (MGI Ref ID J:60223)

• decreased B cell proliferation
  • splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens
  (MGI Ref ID J:60223)

• decreased T cell proliferation
  • splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens
  (MGI Ref ID J:60223)

• increased apoptosis
  • apoptosis of male germ cells and in the GI crypts of late generation mutants
  (MGI Ref ID J:120065)

• increased B cell apoptosis
  • splenocytes from immunized fifth and sixth generation mice exhibit a small increase in apoptosis after mitogen treatment
  (MGI Ref ID J:60223)

• increased cardiomyocyte apoptosis
  • fifth generation mutants exhibit a 63% increase in cardiomyocyte apoptosis
  (MGI Ref ID J:110900)

• increased embryonic tissue cell apoptosis
  • E10.5 embryos with neural tube defects exhibit an increase in apoptosis
  (MGI Ref ID J:53600)

digestive/alimentary phenotype

• abnormal intestine morphology
  • the GI crypts of late generation mutants exhibit high levels of apoptosis
  (MGI Ref ID J:120065)

embryo phenotype

• abnormal developmental patterning
  • a portion of embryos with open neural tube show absence of bilateral symmetry in the brain
  (MGI Ref ID J:53600)

• increased embryonic tissue cell apoptosis
  • E10.5 embryos with neural tube defects exhibit an increase in apoptosis
  (MGI Ref ID J:53600)

• open neural tube
  • a percentage of embryos fail to close the neural tube, particularly in the forebrain and midbrain, at E10.5; penetrance of this defect increases with generation number, with 30% of fifth generation embryos showing an open neural tube
  (MGI Ref ID J:53600)

endocrine/exocrine gland phenotype

• testicular atrophy
  • testicular atrophy and associated apoptotic depletion of germ cells in late generation mutants
  (MGI Ref ID J:120065)

growth/size/body region phenotype

• decreased body size
  • late generation mutants have reduced body size and are fragile
  (MGI Ref ID J:120065)

• decreased body weight
  • late generation mutants have reduced body weight
  (MGI Ref ID J:120065)

• decreased fetal size
  • 41% of homozygous fetuses from late generation pregnant females are reduced in size
  (MGI Ref ID J:89751)

• weight loss
  • older (6-8 months) fifth generation mutants often show sudden losses in body weight
  (MGI Ref ID J:110900)

hematopoietic system phenotype

• abnormal spleen B cell follicle morphology
  • spleens from sixth generation mutants (but not earlier generations) show fewer follicles
  (MGI Ref ID J:60223)

• decreased B cell proliferation
  • splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens
  (MGI Ref ID J:60223)

• decreased spleen germinal center number
  • fifth and sixth generation homozygotes show a reduction in germinal centers following antigen (KLH) immunization
  (MGI Ref ID J:60223)

• decreased T cell proliferation
  • splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens
  (MGI Ref ID J:60223)

• increased B cell apoptosis
  • splenocytes from immunized fifth and sixth generation mice exhibit a small increase in apoptosis after mitogen treatment
  (MGI Ref ID J:60223)

homeostasis/metabolism phenotype

• decreased incidence of tumors by chemical induction
  • first generation mutants are slightly less susceptible to DMBA + TPA induced skin tumorigenesis, with a delay in papilloma formation compared to wild-type and papillomas that do not progress to lesions bigger than 8 mm
  (MGI Ref ID J:96945)

immune system phenotype

• abnormal spleen B cell follicle morphology
  • spleens from sixth generation mutants (but not earlier generations) show fewer follicles
  (MGI Ref ID J:60223)

• decreased B cell proliferation
  • splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens
  (MGI Ref ID J:60223)

• decreased spleen germinal center number
  • fifth and sixth generation homozygotes show a reduction in germinal centers following antigen (KLH) immunization
  (MGI Ref ID J:60223)

• decreased T cell proliferation
  • splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens
  (MGI Ref ID J:60223)

• increased B cell apoptosis
  • splenocytes from immunized fifth and sixth generation mice exhibit a small increase in apoptosis after mitogen treatment
  (MGI Ref ID J:60223)

integument phenotype

• alopecia
  • late generation mutants exhibit alopecia
  (MGI Ref ID J:120065)

mammalian phenotype

• homeostasis/metabolism phenotype
  • Normal - homozygotes exhibit normal wound healing
  (MGI Ref ID J:96945)

mortality/aging

• premature aging
  • late generation mutants exhibit accelerated degeneration as indicated by hair graying, alopecia, kyphosis, reduced body size and weight, and fragility
  (MGI Ref ID J:120065)

• premature death
  • older (6-8 months) fifth generation mutants that show sudden loss in body weight and activity die 7-12 hours after the manifestation of these phenotypes
  (MGI Ref ID J:110900)

• prenatal lethality, incomplete penetrance
  • a fraction of homozygous embryos from late generation homozygous matings do not survive gestation to completion or die immediately after birth
  (MGI Ref ID J:53600)
  • only 74% of homozygous fetuses from late generation pregnant females are alive
  (MGI Ref ID J:89751)

muscle phenotype

• abnormal cardiac muscle contractility
  • fifth generation, but not second generation, mutants exhibit a decrease in +dP/dt
  (MGI Ref ID J:110900)

• abnormal cardiac muscle relaxation
  • fifth generation mutants exhibit a decrease in -dP/dt
  (MGI Ref ID J:110900)

• abnormal fetal cardiomyocyte proliferation
  • second and fifth generation mutants exhibit decreased cardiac myocyte proliferation
  (MGI Ref ID J:110900)

• abnormal myocardial fiber morphology
  • the volume of binucleated cardiomyocytes is increased by 24% in second generation mutants and 52% in fifth generation mutants
  (MGI Ref ID J:110900)
  • the volume of mononucleated cardiomyocytes is increased by 39% and 43% in second and fifth generation mutants, respectively
  (MGI Ref ID J:110900)

• decreased myocardial fiber number
  • cardiomyocyte number is decreased 16% and 49% in second and fifth generation mutants, respectively
  (MGI Ref ID J:110900)

• dilated cardiomyopathy
  • dilated cardiomyopathy develops in fifth generation mutants
  (MGI Ref ID J:110900)

• heart left ventricle hypertrophy
  • fifth generation mutants show a reduction in left ventricle mass that is accompanied by a decrease in left ventricle mass:chamber volume ratio, indicating decompensated eccentric left ventricle hypertrophy in the absence of an absolute increase in ventricular weight
  (MGI Ref ID J:110900)
  • ular weight
  (MGI Ref ID J:110900)

• increased cardiomyocyte apoptosis
  • fifth generation mutants exhibit a 63% increase in cardiomyocyte apoptosis
  (MGI Ref ID J:110900)

neoplasm

• decreased incidence of induced tumors
  • fifth generation mutants show decreased tumor growth rate and lower tumor formation efficiency upon dermal or subcutaneous melanoma cell injection
  (MGI Ref ID J:74001)
  • tumors that are induced in fifth generation mutants show decreased replication potential and increased apoptotic rates
  (MGI Ref ID J:74001)

• decreased incidence of tumors by chemical induction
  • first generation mutants are slightly less susceptible to DMBA + TPA induced skin tumorigenesis, with a delay in papilloma formation compared to wild-type and papillomas that do not progress to lesions bigger than 8 mm
  (MGI Ref ID J:96945)

nervous system phenotype

• open neural tube
  • a percentage of embryos fail to close the neural tube, particularly in the forebrain and midbrain, at E10.5; penetrance of this defect increases with generation number, with 30% of fifth generation embryos showing an open neural tube
  (MGI Ref ID J:53600)

reproductive system phenotype

• abnormal female meiosis
  • in response to telomere shortening, female germ cells arrest in early meiosis
  (MGI Ref ID J:89751)
  • meiocytes of fourth generation (G4) females with shortened telomeres bred with early generation males harboring relatively long telomeres, exhibit severely impaired chromosome pairing and synapsis and reduced meiotic recombination
  (MGI Ref ID J:89751)
  • synaptonemal complex protein 3 (SCP3) elements are altered in G4 female meiotic cells
  (MGI Ref ID J:89751)

• abnormal male germ cell apoptosis
  • apoptotic depletion of germ cells in late generation mutants
  (MGI Ref ID J:120065)
  • in response to telomere shortening, male germ cells undergo apoptosis
  (MGI Ref ID J:89751)

• abnormal male meiosis
  • the number of spermatocytes with synaptonemal complex protein 3 (SCP3) lateral elements is decreased in the fourth generation (G4) homozygotes
  (MGI Ref ID J:89751)

• abnormal meiosis
  • chromosome pairing, synapsis, and recombination are severely impaired in meiocytes with irregular telomeres
  (MGI Ref ID J:89751)

• abnormal oocyte morphology
  • the number of oocytes that form synaptonemal complexes is decreased
  (MGI Ref ID J:89751)

• abnormal spermatocyte morphology
  • apoptosis is increased 5-fold in seminiferous tubules of G4 homozygotes; apoptosis is found in the outer layers of spermatocytes whereas the inner layer of spermatogonia remains intact
  (MGI Ref ID J:89751)

• decreased litter size
  • mutants of late generations show a decrease in litter size
  (MGI Ref ID J:53600)

• infertility
  • Background Sensitivity - mutants are infertile at the sixth generation (of interbreeding) and infertile at the fourth generation of backcrossing to C57BL/6J
  (MGI Ref ID J:53600)

• reduced female fertility
  • late generation pregnant females have fewer fetuses
  (MGI Ref ID J:89751)

• testicular atrophy
  • testicular atrophy and associated apoptotic depletion of germ cells in late generation mutants
  (MGI Ref ID J:120065)

skeleton phenotype

• kyphosis
  • late generation mutants exhibit kyphosis
  (MGI Ref ID J:120065)

cellular phenotype

• abnormal spermatid morphology
  • at 8 months of age, second generation (G2) homozygotes exhibit fewer intact elongating spermatids containing extended telomeres than wild-type or heterozygous littermates
  (MGI Ref ID J:98586)
  • however, fertility is preserved, suggesting that alternative telomere extension activity is capable of partially complementing the telomerase defect
  (MGI Ref ID J:98586)

• abnormal telomere length
  • elongated spermatids from second generation (G2) homozygotes display variable telomere length, with some displaying long telomeres, while others have short telomeres
  (MGI Ref ID J:98586)

reproductive system phenotype

• abnormal spermatid morphology
  • at 8 months of age, second generation (G2) homozygotes exhibit fewer intact elongating spermatids containing extended telomeres than wild-type or heterozygous littermates
  (MGI Ref ID J:98586)
  • however, fertility is preserved, suggesting that alternative telomere extension activity is capable of partially complementing the telomerase defect
  (MGI Ref ID J:98586)

cellular phenotype

• abnormal cell physiology
  • mouse embryonic fibroblasts (MEFs) from third generation mice exhibit decreased immortalization ability under a 3T3 cell passage protocol compared with similarly treated wild-type cells
  (MGI Ref ID J:125218)
  • sister chromatid exchange in MEFs is increased compared to in wild-type cells
  (MGI Ref ID J:125218)

• abnormal DNA repair
  • cells from the small intestine exhibit an increase in gamma-H2AX foci, indicative of DNA damage, compared with cells from wild-type mice
  (MGI Ref ID J:125218)

• abnormal enterocyte proliferation
  • intestinal cell proliferation is impaired compared to in wild-type mice
  (MGI Ref ID J:125218)

• chromosomal instability
  • end-to-end chromosome fusions in MEFs are increased compared to in wild-type cells
  (MGI Ref ID J:125218)
  • MEFs from late generation mice exhibit an increase in chromosome breaks, fragments, bivalent recombination figures, and complex aberrations compared with wild-type cells
  (MGI Ref ID J:125218)
  • mouse embryonic fibroblasts (MEFs) exhibit in increase in microsatellite instability compared with wild-type cells
  (MGI Ref ID J:125218)

• decreased telomere length
  • telomeres become progressively shorter each generation unlike in wild-type mice
  (MGI Ref ID J:125218)

• increased enterocyte apoptosis
  • regardless of generation
  (MGI Ref ID J:125218)

digestive/alimentary phenotype

• abnormal enterocyte proliferation
  • intestinal cell proliferation is impaired compared to in wild-type mice
  (MGI Ref ID J:125218)

• abnormal intestine morphology
  • mice exhibit mild to severe intestinal atrophy unlike wild-type mice that worsens in successive generations
  (MGI Ref ID J:125218)

• increased enterocyte apoptosis
  • regardless of generation
  (MGI Ref ID J:125218)

homeostasis/metabolism phenotype

• abnormal DNA repair
  • cells from the small intestine exhibit an increase in gamma-H2AX foci, indicative of DNA damage, compared with cells from wild-type mice
  (MGI Ref ID J:125218)

mortality/aging

• premature death
  • median survival is reduced in successive generations compared to in wild-type mice
  (MGI Ref ID J:125218)

neoplasm

• increased lymphoma incidence
  • the incidence of lymphomas decreases in successive generation
  (MGI Ref ID J:125218)

adipose tissue phenotype

• abnormal adipose tissue distribution
  • increase in bone marrow fat content in aged mice
  (MGI Ref ID J:213181)

skeleton phenotype

• abnormal bone marrow morphology
  • increase in bone marrow fat content in aged mice
  (MGI Ref ID J:213181)

• abnormal bone ossification
  • mineralized surface, mineral apposition rate, and bone formation rate dramatically decline with age
  (MGI Ref ID J:213181)

• abnormal compact bone morphology
  • 27.1% and 49.3% increase in cortical porosity in young and aged mice, respectively
  (MGI Ref ID J:213181)

• abnormal osteoid morphology
  • osteoid significantly decreases with age
  (MGI Ref ID J:213181)

• abnormal skeleton physiology
  • bone shows mechanical alterations including an increase in structure model index, a decrease in anisotropy and a decrease in the moment of inertia
  (MGI Ref ID J:213181)

• decreased bone trabecula number
  • young femurs show a more rod-like trabecular structure
  (MGI Ref ID J:213181)

• decreased bone volume
  • 41.7% and 84.9% decrease in femur bone volume at 3 months of age and in aged mice, respectively
  (MGI Ref ID J:213181)

• decreased compact bone area
  • 4% and 28.2% decrease in cortical bone area in young and aged mice, respectively
  (MGI Ref ID J:213181)

• decreased compact bone thickness
  • decrease in cortical thickness in both young and aged mice
  (MGI Ref ID J:213181)

• decreased trabecular bone thickness
  (MGI Ref ID J:213181)

• increased bone trabecular spacing
  • increase in trabecular separation
  (MGI Ref ID J:213181)

• osteoporosis
  • accelerated bone aging characteristic features of human senile osteoporosis
  (MGI Ref ID J:213181)