Analysis Tools
mortality/aging
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• 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
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• a fraction of homozygous embryos from late generation homozygous matings do not survive gestation to completion or die immediately after birth
(J:53600)
• only 74% of homozygous fetuses from late generation pregnant females are alive
(J:89751)
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• late generation mutants exhibit accelerated degeneration as indicated by hair graying, alopecia, kyphosis, reduced body size and weight, and fragility
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cellular
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• second and fifth generation mutants exhibit decreased cardiac myocyte proliferation
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• the number of oocytes that form synaptonemal complexes is decreased
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• 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
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• lack of perinuclear distribution of telomeres in fourth generation mutants
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• 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
(J:43517)
• splenocytes from non-immunized fifth generation mutants contain shorter telomere lengths than wild-type
(J:60223)
• 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
(J:60223)
• telomere shortening occurs in both meiocytes with normal and abnormal synapsis
(J:89751)
• keratinocytes exhibit a significant decrease in average telomere length compared with wild-type cells
(J:96945)
• cardiac myocytes of second and fifth generation mutants show telomere shortening, with cardiomyocytes from older mutants having shorter telomeres than in younger mutants
(J:110900)
• the anaphase bridge index (ABI) is increased in late-generation (G4/G5) intestinal crypts indicating telomere dysfunction
(J:120065)
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• chromosome pairing, synapsis, and recombination are severely impaired in meiocytes with irregular telomeres
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• in response to telomere shortening, female germ cells arrest in early meiosis
• 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
• synaptonemal complex protein 3 (SCP3) elements are altered in G4 female meiotic cells
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• the number of spermatocytes with synaptonemal complex protein 3 (SCP3) lateral elements is decreased in the fourth generation (G4) homozygotes
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• apoptosis of male germ cells and in the GI crypts of late generation mutants
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• fifth generation mutants exhibit a 63% increase in cardiomyocyte apoptosis
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• splenocytes from immunized fifth and sixth generation mice exhibit a small increase in apoptosis after mitogen treatment
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• E10.5 embryos with neural tube defects exhibit an increase in apoptosis
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• in response to telomere shortening, male germ cells undergo apoptosis
(J:89751)
• apoptotic depletion of germ cells in late generation mutants
(J:120065)
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• splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens
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• splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens
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neoplasm
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• fifth generation mutants show decreased tumor growth rate and lower tumor formation efficiency upon dermal or subcutaneous melanoma cell injection
• tumors that are induced in fifth generation mutants show decreased replication potential and increased apoptotic rates
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• 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
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cardiovascular system
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• late generation mutants show decreased angiogenic potential in a basement membrane matrix assay
• microvessel density is decreased in the induced tumors of fifth generation mutants
• large abnormal vessels are present in the induced tumors of fifth generation mutants
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• the volume of binucleated cardiomyocytes is increased by 24% in second generation mutants and 52% in fifth generation mutants
• the volume of mononucleated cardiomyocytes is increased by 39% and 43% in second and fifth generation mutants, respectively
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• cardiomyocyte number is decreased 16% and 49% in second and fifth generation mutants, respectively
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• heart weight is decreased in fifth generation mutants
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• fifth generation mutants exhibit cardiac myocyte hypertrophy
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• 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
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• left ventricle weight is decreased in fifth generation mutants
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• fifth generation, but not second generation, mutants suffer from a severe left ventricular failure
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• dilated cardiomyopathy develops in fifth generation mutants
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• fifth generation, but not second generation, mutants exhibit a decrease in +dP/dt
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• fifth generation mutants exhibit a decrease in -dP/dt
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• second and fifth generation mutants exhibit decreased cardiac myocyte proliferation
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• fifth generation mutants exhibit a decrease in LV developed pressure
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• fifth generation mutants exhibit an elevation of LV end-diastolic pressure
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• fifth generation mutants exhibit a 63% increase in cardiomyocyte apoptosis
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• older fifth generation mutants die of heart failure
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hematopoietic system
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• splenocytes from immunized fifth and sixth generation mice exhibit a small increase in apoptosis after mitogen treatment
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• splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens
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• splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens
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• spleens from sixth generation mutants (but not earlier generations) show fewer follicles
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• fifth and sixth generation homozygotes show a reduction in germinal centers following antigen (KLH) immunization
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immune system
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• splenocytes from immunized fifth and sixth generation mice exhibit a small increase in apoptosis after mitogen treatment
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• splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens
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• splenocytes (from both non-immunized and immunized) from sixth generation mutants show a decrease in the proliferative response to B and T cell mitogens
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• spleens from sixth generation mutants (but not earlier generations) show fewer follicles
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• fifth and sixth generation homozygotes show a reduction in germinal centers following antigen (KLH) immunization
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embryo
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• E10.5 embryos with neural tube defects exhibit an increase in apoptosis
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• a portion of embryos with open neural tube show absence of bilateral symmetry in the brain
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• 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
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nervous system
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• 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
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reproductive system
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• the number of oocytes that form synaptonemal complexes is decreased
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• 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
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• chromosome pairing, synapsis, and recombination are severely impaired in meiocytes with irregular telomeres
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• in response to telomere shortening, female germ cells arrest in early meiosis
• 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
• synaptonemal complex protein 3 (SCP3) elements are altered in G4 female meiotic cells
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• the number of spermatocytes with synaptonemal complex protein 3 (SCP3) lateral elements is decreased in the fourth generation (G4) homozygotes
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• in response to telomere shortening, male germ cells undergo apoptosis
(J:89751)
• apoptotic depletion of germ cells in late generation mutants
(J:120065)
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• testicular atrophy and associated apoptotic depletion of germ cells in late generation mutants
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• late generation pregnant females have fewer fetuses
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• mutants of late generations show a decrease in litter size
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infertility
(
J:53600
)
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• Background Sensitivity: mutants are infertile at the sixth generation (of interbreeding) and infertile at the fourth generation of backcrossing to C57BL/6J
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behavior/neurological
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• older (6-8 months) fifth generation mutants often show a sudden decrease in activity
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growth/size/body
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• fifth generation mutants exhibit cardiac myocyte hypertrophy
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• 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
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• late generation mutants have reduced body size and are fragile
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• late generation mutants have reduced body weight
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weight loss
(
J:110900
)
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• older (6-8 months) fifth generation mutants often show sudden losses in body weight
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• 41% of homozygous fetuses from late generation pregnant females are reduced in size
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muscle
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• the volume of binucleated cardiomyocytes is increased by 24% in second generation mutants and 52% in fifth generation mutants
• the volume of mononucleated cardiomyocytes is increased by 39% and 43% in second and fifth generation mutants, respectively
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• cardiomyocyte number is decreased 16% and 49% in second and fifth generation mutants, respectively
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• 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
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• dilated cardiomyopathy develops in fifth generation mutants
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• fifth generation, but not second generation, mutants exhibit a decrease in +dP/dt
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• fifth generation mutants exhibit a decrease in -dP/dt
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• second and fifth generation mutants exhibit decreased cardiac myocyte proliferation
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• fifth generation mutants exhibit a 63% increase in cardiomyocyte apoptosis
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homeostasis/metabolism
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• homozygotes exhibit normal wound healing
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• 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
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digestive/alimentary system
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• the GI crypts of late generation mutants exhibit high levels of apoptosis
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skeleton
integument
endocrine/exocrine glands
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• testicular atrophy and associated apoptotic depletion of germ cells in late generation mutants
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