Analysis Tools
mortality/aging
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• 50% of homozygotes die by 17 months of age
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neoplasm
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• 80.7% (21 of 26) of homozygotes develop tumors by 16-18 months of age relative to only 37% (10 of 27) heterozygotes mice and 37.5% (9 of 24) of wild-type mice
• the majority of homozygotes (69.2%) develop lymphomas although other tumors are observed at a reduced frequency that is not significantly different from that observed in wild-type mice
• notably, 42.3% (11 of 26) of homozygotes develop two or more different types of tumor at the same time whereas only 11% (3 of 27) of heterozygotes and 0% (0 of 24) of wild-type mice develop more than one different tumor type
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• 69.2% (18 of 26) of homozygotes display lymphomas relative to 29.6% (8 of 27) heterozygotes and 20.8% (5 of 24) wild-type mice
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reproductive system
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• while mutant ocytes progress normally through early prophase I of meiosis into early diplotene and enter dictyate arrest a few days after birth, homozygotes exhibit oocyte loss at 7 months of age
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• epididymal sperm counts indicate that adult male homozygotes contain ~50 spermatozoa per male relative to 8 107 spermatozoa per wild-type male
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• although some crossovers occur, the majority of chromosome preparations from mutant spermatocytes are either univalents or appear to be achiasmate or abnormal bivalents
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• 17% of the remaining bivalent chromosomes are achiasmate, indicating a specific loss of chiasmata at metaphase I that results in checkpoint activation and apoptosis
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• air-dried chromosome preparations from mutant spermatocytes exhibit aberrant metaphase configurations with >75% of chromosomes being univalents instead of the expected chiasmate bivalents, while the remaining chromosomes are bivalents
• 17% of the remaining bivalent chromosomes are achiasmate, 15% are morphologically abnormal, while the rest appear normal
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• by metaphase, mutant spermatocytes exhibit abnormal spindle structures within the seminiferous tubules, with chromosomes misaligned across the spindles
• however, mutant spermatocytes display normal chromosomal pairing and synapsis at pachynema, indicating normal progression from leptotene through pachytene during meiosis I in adult males
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• the majority of mutant spermatocytes become apoptotic at metaphase, as indicated by significantly higher numbers of TUNEL-positive cells within the lumen of seminiferous tubules in adult males
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• a very small number of nonmotile spermatozoa can be retrieved from the epididymides of adult male homozygotes
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• at 7 months of age, homozygotes show significant heterogeneity in ovarian size and morphology, both within the same animal and between age-matched females
• however, no differences in ovarian size or content are noted at 10 weeks of age
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small ovary
(
J:82426
)
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• at 7 months of age, mutant ovaries are often smaller than wild-type ovaries
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small testis
(
J:82426
)
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• in adult homozygotes, testis size is only ~30%-50% of that in wild-type and heterozygote littermates
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• despite normal progression through prophase I, resulting oocytes are not capable of postfertilization development and female homozygotes are infertile when mated with wild-type males
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• male homozygotes are infertile when mated with wild-type females
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cellular
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• while mutant ocytes progress normally through early prophase I of meiosis into early diplotene and enter dictyate arrest a few days after birth, homozygotes exhibit oocyte loss at 7 months of age
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• epididymal sperm counts indicate that adult male homozygotes contain ~50 spermatozoa per male relative to 8 107 spermatozoa per wild-type male
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• although some crossovers occur, the majority of chromosome preparations from mutant spermatocytes are either univalents or appear to be achiasmate or abnormal bivalents
|
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• 17% of the remaining bivalent chromosomes are achiasmate, indicating a specific loss of chiasmata at metaphase I that results in checkpoint activation and apoptosis
|
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• air-dried chromosome preparations from mutant spermatocytes exhibit aberrant metaphase configurations with >75% of chromosomes being univalents instead of the expected chiasmate bivalents, while the remaining chromosomes are bivalents
• 17% of the remaining bivalent chromosomes are achiasmate, 15% are morphologically abnormal, while the rest appear normal
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• by metaphase, mutant spermatocytes exhibit abnormal spindle structures within the seminiferous tubules, with chromosomes misaligned across the spindles
• however, mutant spermatocytes display normal chromosomal pairing and synapsis at pachynema, indicating normal progression from leptotene through pachytene during meiosis I in adult males
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• the majority of mutant spermatocytes become apoptotic at metaphase, as indicated by significantly higher numbers of TUNEL-positive cells within the lumen of seminiferous tubules in adult males
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• a very small number of nonmotile spermatozoa can be retrieved from the epididymides of adult male homozygotes
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• in vitro, extracts from mutant ES cells fail to exhibit either 5'- or 3'-nick-directed base:base and single-base insertion/deletion mismatch repair activity
• in constrast, significant mismatch repair is detected with substrates containing dinucleotide insertion/deletion loop mispairs
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• tail DNA from mutant mice exhibits a significant increase in microsatellite instability at a mononucleotide repeat marker (U12235) relative to that observed in wild-type mice (14% vs 3%, respectively)
• in addition, mutant ES cells show a 30-fold increase in the mutation rate at the Hprt locus relative to wild-type cells
• in contrast to the mononucleotide repeat marker, no significant microsatellite instability is observed at two dinucleotide markers (D7Mit91 and D17Mit123)
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endocrine/exocrine glands
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• at 7 months of age, homozygotes show significant heterogeneity in ovarian size and morphology, both within the same animal and between age-matched females
• however, no differences in ovarian size or content are noted at 10 weeks of age
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small ovary
(
J:82426
)
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• at 7 months of age, mutant ovaries are often smaller than wild-type ovaries
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small testis
(
J:82426
)
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• in adult homozygotes, testis size is only ~30%-50% of that in wild-type and heterozygote littermates
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homeostasis/metabolism
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• in vitro, extracts from mutant ES cells fail to exhibit either 5'- or 3'-nick-directed base:base and single-base insertion/deletion mismatch repair activity
• in constrast, significant mismatch repair is detected with substrates containing dinucleotide insertion/deletion loop mispairs
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