Analysis Tools
mortality/aging
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• mice exhibit a shortened life span; only a few reach an age of 32 days
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• mean survival is 18.3 +/- 7.7 days, with some mice dying early postnatally
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growth/size/body
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• at P23 and P32, the tongue shows hyperkeratosis, fewer papillae, disorganized architecture, and nuclear pleomorphism
• however, no visible white plaques are observed macroscopically on the tongue surface
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• body size is slightly reduced at birth (P0.5)
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• mean body weight is already reduced at P0.5
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• all mice develop severe failure to thrive soon after P0.5, with further reduction in body weight at P20-P23
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cellular
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• at P23, Q-FISH analysis shows a markedly lower number of telomeric foci per nucleus in the liver, lung, and small intestine but not in the cerebellum; distribution of the mean nuclear telomere intensity indicates decreased median and lower quartile values in all four tissues analyzed
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• at P23, qPCR analysis shows decreased telomere length across various tissues, including the cerebrum, cerebellum, liver, and lung; skin shows an age-related reduction with more pronounced telomere shortening noted at P23 than at P5
• at P23, Q-FISH analysis shows that the mean nuclear telomere length is reduced by 8%, 15%, 6%, and 23% in the cerebellum, liver, lung, and small intestine, respectively
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• RT- qPCR shows increased mRNA abundance of four retrotransposon classes [long interspersed nuclear element 1 (LINE1), MusD, B1, and B2] in the liver and lung at P23
• however, no increase in transposon transcription is detected in the cerebrum, cerebellum, or skin
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• TUNEL staining indicates increased apoptosis in the cerebellum at P5 and in skin and crypts of the small intestine at P23
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• TUNEL staining indicates increased apoptosis in the cerebellum at P5
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• TUNEL staining indicates increased apoptosis in the crypts of the small intestine at P23
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• RT-qPCR analysis shows a significant decrease in Mki67 mRNA expression level in the liver, lung, and skin at P23, along with a non-significant reduction in the cerebrum but no change in the cerebellum
• IHC shows fewer Ki67+ proliferating cells in cerebellum at P5 and in skin and small intestine at P23
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• IHC of p53 and downstream cell cycle arrest protein p21 indicates that both are highly expressed at P5 in the cerebellum, at P23 in the small intestine, and at both time points in the spleen
• RT-qPCR shows an increased Trp53 (encoding p53) expression in cerebellum at P23 while Cdkn1a (encoding p21) is up-regulated in cerebrum, liver, lung, and skin
• a number of cellular senescence-associated transcripts are upregulated in several tissues but to a variable extent: an induction of senescence is seen in skin (upregulated p16Ink4a and loss of Lmnb1), cerebrum (upregulated p19Arf and loss of Lmnb1), liver (upregulated Bcl2 and Bhlhe40, and loss of Lmnb1), and lung (upregulated Bcl2) at P23
• in contrast, a significant inhibition of senescence at P23 is only found in the liver (downregulated p16Ink4a and p19Arf)
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• a mild DNA damage response is detected at P23, with higher pH2AX and pATM in the small intestine and elevated pATR in liver
• however, no differences in pATM or pATR abundance are detected in lung
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integument
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• flank skin hypodermis appears thinner at P23
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• IHC for stem cell marker Sox9 shows loss of Sox9+ cells in skin at P32
• analysis of CK15 by IHC in flank skin indicates a similar tendency at P32
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• flank skin dermis appears thinner at P23
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• tongue hyperkeratosis at P23 and P32
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• at P23, skin pigmentation is increased in palmar and plantar aspects of the fore- and hindpaws, with walking pads being especially affected
• snout and flank skin sections show progressive accumulation of melanin, mainly in hair follicle remnants but also focally in the epidermis
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pigmentation
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• at P23, skin pigmentation is increased in palmar and plantar aspects of the fore- and hindpaws, with walking pads being especially affected
• snout and flank skin sections show progressive accumulation of melanin, mainly in hair follicle remnants but also focally in the epidermis
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digestive/alimentary system
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• TUNEL staining indicates increased apoptosis in the crypts of the small intestine at P23
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• at P23 and P32, the tongue shows hyperkeratosis, fewer papillae, disorganized architecture, and nuclear pleomorphism
• however, no visible white plaques are observed macroscopically on the tongue surface
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• at P23, the small intestine shows signs of mucosal atrophy
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• IHC for stem cell marker Sox9 shows loss of Sox9+ cells in the small intestine at P32
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• at P23, the small intestine shows reduced villi length and signs of mucosal atrophy
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nervous system
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• TUNEL staining indicates increased apoptosis in the cerebellum at P5
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• IHC for stem cell marker Sox9 shows an obvious loss of Sox9+ cells in the cerebellum as early as P5
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• at P23, instead of the single layer of well-ordered Purkinje (calbindin-positive) cells observed in controls, several layers of cells are often found stacked together in a disorganized pattern
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• a marked reduction in granular neuron (NeuN-positive) cell number is noted at P23
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• cerebellar hypoplasia is already evident at P5 and becomes more pronounced at P23
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hematopoietic system
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• at P23, the thymus cortex shows decreased cellularity and appears pale
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• a dark basophilic thymus medulla is observed at P23
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• at P23, mice show thymic atrophy with decreased cellularity of the cortex (appearing pale) and a dark basophilic medulla
• however, no atrophic changes are noted in the thymus at P5
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• at P23, femoral bone marrow displays features of aplastic anemia, characterized by the replacement of hematopoietic cells (including erythroid, lymphoid, and myeloid progenitors) with stromal adipose tissue
• at P5, bone marrow shows only a slight reduction in the number of hematopoietic cells, indicating a progressive hematological defect
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• at P23
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vision/eye
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• at P9, the iris is completely attached to the cornea, resulting in severe synechia
• however, the iris and the cornea appear to be almost separate by P21
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• a thinner cornea is noted at P21
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• retina exhibits rosette-like alterations that progress in severity from P9 to P21
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• fewer cell nuclei are detected in the retina inner nuclear layer at P21
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• fewer cell nuclei are detected in the retina outer nuclear layer at P21
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• total retina thickness is reduced at P21, with little change observed over time
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• at P21
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behavior/neurological
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• mice exhibit reduced locomotion starting around P10
• however, the behavior of newborn pups appears normal
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immune system
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• at P23, the thymus cortex shows decreased cellularity and appears pale
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• a dark basophilic thymus medulla is observed at P23
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• at P23, mice show thymic atrophy with decreased cellularity of the cortex (appearing pale) and a dark basophilic medulla
• however, no atrophic changes are noted in the thymus at P5
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• at P23
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• expression of proinflammatory cytokines Ifng, Il1b, Il6, and Tnf is upregulated in the cerebrum; similar patterns are noted in the cerebellum, liver, lung, and skin, although not all parameters examined reach statistical significance
• Tnf expression is downregulated in the lung
• expression of chemokine Ccl2 is significantly upregulated in the cerebellum, liver, and skin, but no differences are found in the cerebrum and lung
• increased expression levels of anti-inflammatory cytokines Il4, Il10, and Il13 are detected in many of the tissues at P23
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• increased inflammation is detected in several organs at P23
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craniofacial
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• at P23 and P32, the tongue shows hyperkeratosis, fewer papillae, disorganized architecture, and nuclear pleomorphism
• however, no visible white plaques are observed macroscopically on the tongue surface
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endocrine/exocrine glands
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• IHC for stem cell marker Sox9 shows loss of Sox9+ cells in the small intestine at P32
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• at P23, the thymus cortex shows decreased cellularity and appears pale
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• a dark basophilic thymus medulla is observed at P23
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• at P23, mice show thymic atrophy with decreased cellularity of the cortex (appearing pale) and a dark basophilic medulla
• however, no atrophic changes are noted in the thymus at P5
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homeostasis/metabolism
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• a mild DNA damage response is detected at P23, with higher pH2AX and pATM in the small intestine and elevated pATR in liver
• however, no differences in pATM or pATR abundance are detected in lung
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skeleton
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• no skeletal defects are detected by micro-computed tomography at P26, apart from size differences
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• mice show a marked reduction in the number of hypertrophic chondrocytes in the tibial growth plates from P5 to P23
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| dyskeratosis congenita | DOID:2729 |
OMIM:PS127550 |
J:365069 | |
