Analysis Tools
mortality/aging
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• despite normal numbers of implantation sites in early pregnancy, homozygotes exhibit fetal loss during the second half of gestation and in the perinatal period
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• during the first 3 weeks of life, the survival rate of pups is affected by parental genotype, with 91.1% survival of pups born to homozygous females vs 98.0% survival of pups born to heterozygous females
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• despite normal numbers of implantation sites in early pregnancy, homozygotes exhibit fetal loss during the second half of gestation and in the perinatal period
• on day 17 of pregnancy, the mean number of resorbing and malformed embryos is twice as high in pregnant female homozygotes (21%) vs female heterozygotes (11%)
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embryo
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• on day 15 of pregnancy, mutant placentas exhibit a 22% increase in the area occupied by the spongiotrophoblast relative to wild-type placentas
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• the proportion of vacuolated trophoblast glycogen cells in the mutant spongiotrophoblast zone is reduced by 20%
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• on day 15 of pregnancy, mutant placentas exhibit a 13% reduction in the area occupied by the labyrinth relative to wild-type placentas
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• mutant placentas show a ~28% reduction in the ratio of labyrinthine to spongiotrophoblast areas
• structural changes in placental architecture are associated with diminished nutrient transfer and appear to contribute to embryonic growth retardation
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immune system
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• by 24 weeks, mutant intraalveolar macrophages exhibit phagosomes with "onion-like" structures resembling type-C lamellar bodies
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• on day 7 postinfection, P. chabaudi AS-infected homozygotes exhibit impaired development of malarial splenomegaly relative to wild-type mice
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• during the periovulatory period, homozygotes exhibit a normal size and composition of ovarian leukocyte populations in the stroma and follicle theca
• however, the number of macrophages/dendritic cells expressing MHC class II (Ia) is significantly reduced in mutant ovaries at ovulation
• after parturition, the number of ovarian macrophages and neutrophils is significantly decreased, with significantly reduced CD11b+ (Mac-1) staining in the stromal region
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• during the postpartum period, mutant ovaries exhibit reduced recruitment of macrophages and neutrophils in the stromal region
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• at ovulation, mutant ovarian macrophages and/or dendritic cells exhibit reduced MHC class II (Ia) expression, suggesting impaired macrophage activation within the ovarian stroma and theca
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• by 11 weeks, mutant lungs display moderate to extensive lymphoid hyperplasia around central and peripheral vessels
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• starting at ~3 weeks, all homozygotes exhibit a nonfatal lung pathology, with local accumulation of surfactant protein within alveoli and a high incidence of bacterial and fungal infection resembling human alveolar proteinosis
• by 12-16 weeks, mutant lungs display extensive peribronchovascular infiltration with lymphocytes, primarily B cells and ~20% T cells (mostly CD4+)
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• one 4-week-old homozygote has been shown to die of purulent acute Pasteurella pneumotropica lobar pneumonia
(J:18747)
• Gram-positive coccobacilli are detected in 7-week-old pneumonic consolidated areas
(J:18747)
• virgin homozygotes exhibit an increased incidence of subclinical bacterial colonization of the uterus, with Pasteurella pneumotropica recovered from 50% of mutant uteri; clearance of bacterial organisms from the reproductive tract occurs normally after mating
(J:53659)
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• at 16 weeks, 3 of 15 mutant lungs contain foci of infection with Grocott-positive fungal particles
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• homozygotes are more susceptible to infection with P. chabaudi AS, as shown by higher peak parasitemia, recurrent recrudescent parasitemia, and significantly increased mortality relative to wild-type mice
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respiratory system
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• starting at ~3 weeks, all homozygotes exhibit a nonfatal lung pathology, with local accumulation of surfactant protein within alveoli and a high incidence of bacterial and fungal infection resembling human alveolar proteinosis
• by 12-16 weeks, mutant lungs display extensive peribronchovascular infiltration with lymphocytes, primarily B cells and ~20% T cells (mostly CD4+)
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• by 24 weeks, mutant intraalveolar macrophages exhibit phagosomes with "onion-like" structures resembling type-C lamellar bodies
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• at 6-12 weeks, mutant alveoli contain large foamy macrophages, neutrophils, and eosinophilic alveolar debris
• surfactant-producing type-II alveolar cells are readily identifiable by their cytoplasmic type-C lamellar bodies
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• granular refractile PAS-positive homogenous eosinophilic material in
contiguous alveoli, resembling material seen in alveolar proteinosis
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• a number of older homozygotes display lungs with enlarged alveolar spaces, suggestive of emphysematous processes with peristent peribronchovascular lymphoid hyperplasia
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hematopoietic system
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• up to 12 weeks of age, homozygotes develop normally and exhibit no major perturbations of hemopoiesis or significant changes in populations of leukocytes in blood, bone marrow, or spleen
• an observed increase in splenic progenitor cell number is thought to reflect subclinical pulmonary infection
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• by 24 weeks, mutant intraalveolar macrophages exhibit phagosomes with "onion-like" structures resembling type-C lamellar bodies
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• on day 7 postinfection, P. chabaudi AS-infected homozygotes exhibit impaired development of malarial splenomegaly relative to wild-type mice
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• during the periovulatory period, homozygotes exhibit a normal size and composition of ovarian leukocyte populations in the stroma and follicle theca
• however, the number of macrophages/dendritic cells expressing MHC class II (Ia) is significantly reduced in mutant ovaries at ovulation
• after parturition, the number of ovarian macrophages and neutrophils is significantly decreased, with significantly reduced CD11b+ (Mac-1) staining in the stromal region
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• during the postpartum period, mutant ovaries exhibit reduced recruitment of macrophages and neutrophils in the stromal region
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• at ovulation, mutant ovarian macrophages and/or dendritic cells exhibit reduced MHC class II (Ia) expression, suggesting impaired macrophage activation within the ovarian stroma and theca
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reproductive system
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• homozygotes exhibit impaired ovarian follicle maturation
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• on day 4 of natural pregnancy, homozygotes show a significant reduction in ovarian weight relative to wild-type mice
• in contrast, the number of corpora lutea remains normal
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• homozygotes exhibit normal uterine development with no discernible differences in the process of decidualization and normal size and distribution of uterine granulocyte and macrophage populations during the estrous cycle, early pregnancy, and midgestation
• however, recently mated or parous mice are occasionally found to have chronic uterine abscesses, as a result of Pasteurella pneumotropica infection
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• in vitro, 70% of wild-type ovaries perfused with LH ovulate one or more oocytes vs 93% of homozygous mutant ovaries; the mean number of oocytes ovulated per mutant ovary is 2.8-fold higher but addition of rmGM-CSF has no effect on the ovulation rate in mutant ovaries
• in vitro, LH-perfused mutant ovaries show a 57% increase in nitrate/nitrite secretion relative to media-perfused and LH-perfused wild-type ovaries; addition of rmGM-CSF to mutant ovaries does not increase NO liberation
• however, immature homozygotes primed with gonadotropins and naturally cycling adult homozygotes exhibit normal ovulation rates relative to wild-type counterparts
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• a significantly longer diestrus stage is observed
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• a significantly longer metestrus-2 stage is observed
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• in homozygotes, the mean duration of estrous cycle is extended by 1.5 days, with a significantly longer metestrus-2 and/or diestrus stage relative to wild-type mice
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• homozygotes display impaired luteinization and steroidogenic function of the corpus luteum during early pregnancy, as a result of altered recruitment and activation of ovarian myeloid leukocytes
• notably, homozygotes exhibit no differences in the time frame of corpus luteum demise, as the length of pseudopregnancy is comparable to that observed in wild-type mice
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• homozygotes display a moderate decrease in fertility, manifested as a 25% reduction in litter size at weaning
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• the mean litter sizes of homozygous mutant breeding pairs are 25% smaller at weaning compared with heterozygous pairs, due to fetal death late in gestation and early in postnatal life
• reduced litter size appears to reflect a selective loss of male pups, with approximately one male less per litter weaned from homozygous mutant females than from heterozygous females
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growth/size/body
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• at weaning, surviving homozygous mutant pups are significantly smaller than wild-type pups
• in males, reduced body size persists into adulthood
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• homozygotes exhibit slow growth kinetics after birth
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• on day 17 of pregnancy, the number of very small fetuses (< 500 mg) is 9-times as high in pregnant female homozygotes (23%) vs female heterozygotes (2.5%)
• the mean fetal weight and the mean fetal:placental ratio in surviving conceptuses are reduced by 7% and 6%, respectively
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• homozygotes exhibit slow growth kinetics in utero
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endocrine/exocrine glands
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• homozygotes exhibit impaired ovarian follicle maturation
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• on day 4 of natural pregnancy, homozygotes show a significant reduction in ovarian weight relative to wild-type mice
• in contrast, the number of corpora lutea remains normal
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homeostasis/metabolism
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• on day 4 of natural pregnancy, adult homozygotes exhibit significantly reduced plasma progesterone levels (116.5 6 nM) relative to wild-type mice (141.6 10.3 nM)
• however, no major alterations in steroid secretion are noted at ovulation
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• granular refractile PAS-positive homogenous eosinophilic material in
contiguous alveoli, resembling material seen in alveolar proteinosis
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cellular
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• during the postpartum period, mutant ovaries exhibit reduced recruitment of macrophages and neutrophils in the stromal region
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• litter sizes in homozygous deficient mothers are less severely affected in pregnancies sired by wild-type males, with resorption rates, fetal weights, and fetal:placental ratios being more comparable to normal values
• conversely, fetal weights and fetal:placental ratios are not reduced in homozygous deficient embryos gestating in replete mothers
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| pulmonary alveolar proteinosis | DOID:12120 |
OMIM:265120 OMIM:300770 OMIM:610913 OMIM:610921 OMIM:614370 |
J:18747 | |
