Analysis Tools
mortality/aging
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• homozygous null mice died in a state of anorexia at P26 plus/minus one day
(J:28201)
• treatment of L-NAME (a strong competitive NOS inhibitor) significantly prolonged the survival of homozygous null mice, but did not abrogate their death
(J:71688)
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behavior/neurological
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• homozygous null mice died in a state of anorexia at around P26
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• during the last days of life, homozygous null mutant mice also displayed progressive atactic gait disturbance
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bradykinesia
(
J:28201
)
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• during the last days of life, homozygous null mutant mice exhibited reduction of spontaneous locomotion and escape reactions
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• at about P20, homozygous null mice began to display neurological phenotypes with repetitive seizures; they began to tremble and move on their tiptoes with a stiff tail
(J:64892)
• most of L-NAME-treated mutant mice still displayed signs of seizure
(J:71688)
|
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• in some cases, mutant mice suffered from severe tonic seizures and died as a result of respiratory arrest
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cellular
| N |
• cultured fibroblasts from homozygous null embryos displayed normal bulk proteolysis in the lysosomal compartment
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• at the terminal stage, the CNS of homozygous null mice exhibited cell death as shown by the appearance of TUNEL-positive cells, especially in the thalamus
• chronic treatment of L-NAME (a strong competitive NOS inhibitor) or SMT (an Nos2 inhibitor) partially but significantly decreased the number of TUNEL-positive cells in the thalamus at the terminal stage, without affecting the number of TUNEL-positive cells in the dentate gyrus of the hippocampus
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• in vivo, mutant CNS neurons exhibited a new form of lysosomal accumulation disease with a phenotype similar to neuronal ceroid lipofuscinosis
• mutant CNS neurons displayed storage of autophagosome/autolysosome-like bodies with part of the cytoplasm, granular osmiophilic deposits, and fingerprint profiles; these bodies emitted autofluorescence and were shown to contain ceroid lipofuscin
• autophagosome/autolysosome-like bodies appeared at P1 but were very small in number, they became prominent in the thalamic region and the cerebral cortex at P17, and they accumulated in the perikarya of almost all neurons after P23
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digestive/alimentary system
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• by P25, the atrophy of the ileal mucosa had progressed and the overall architecture of the mucosa was abnormal
(J:28201)
• the number of villi was reduced, the ratio between diameter and height of the villi was decreased, and the limit between epithelium and central connective tissue normally formed by a well-defined basement membrane was absent
(J:28201)
• the lamina propria appeared narrow, thus blood or lymphatic vessels were rarely detected
(J:28201)
• unexpectedly, chronic treatment of L-NAME or SMT significantly improved the severe hemorrhage-necrotic alterations in the small intestine and atrophic changes of the ileal mucosa
(J:71688)
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• the mean diameter of the crypts of Lieberkuhn was reduced and their secretory ducts were atrophic
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• most major organs (including liver, heart, lung, kidney, intestine, pancreas, brain, spleen and thymus) appeared normal until P14, when atrophic changes of the ileal mucosa were first observed
• autopsy revealed necrosis of the small intestine in terminally affected animals
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endocrine/exocrine glands
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• the mean diameter of the crypts of Lieberkuhn was reduced and their secretory ducts were atrophic
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• the thymus appeared histologically normal at P14; however, lymphoid cells were almost entirely absent in the cortex by P25
• stromal cells were prominent and necrotic cell disease was visible in the medulla
• at P14, the number of thymic cells undergoing apoptosis was increased significantly and was further elevated at P25
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growth/size/body
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• homozygous null mice were viable and displayed no phenotypic abnormalities during the first two weeks of life; however, their weight started to decline on entering the 4th week
(J:28201)
• at P25, the mean weight of homozygous null mice was only ~60% of that of wild-type littermates
(J:28201)
• unexpectedly, chronic treatment of L-NAME (a strong competitive NOS inhibitor) or SMT (an Nos2 inhibitor) completely suppressed the body weight reduction of homozygotes after P14
(J:71688)
|
hematopoietic system
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• the thymus appeared histologically normal at P14; however, lymphoid cells were almost entirely absent in the cortex by P25
• stromal cells were prominent and necrotic cell disease was visible in the medulla
• at P14, the number of thymic cells undergoing apoptosis was increased significantly and was further elevated at P25
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• homozygous null mice displayed loss of lymphocytes in the spleen and thymus
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• flow cytometric analysis showed that the percentage of CD4+/CD8+ double-positive immature T cells was reduced considerably in P24-P26-day-old affected animals; splenocytes were reduced to a comparable extent at P25 and P26, while the percentage of lymphocytes gated was only moderately reduced and the proportion of IgM/B220+ B cells remained unaffected
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• after P16, the cerebral cortex and thalamus of homozygous null mice displayed a significant accumulation of morphologically abnormal microglia, which had expanded and round cell bodies with few thick processes
• by P24, transformed microglia in the cortex and the thalamus displayed enhanced phagocytic activity: they phagocytosed damaged storage neurons laden with ceroid-lipofuscin
• after P20, activated microglia exhibited significant expression of macrophage, inducible nitric oxide synthase-2 (Nos2)
• at P24, homozygotes showed significant accumulation of NO2- (a major metabolite of nitric oxide) and elevated expression of Nos2 in cytosolic fractions of the brain and small intestine
• neither the accumulation of ceroid-lipofuscin in neurons nor the microglial phagocytic activity was affected by chronic treatment of L-NAME or SMT
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• at P25 and P26, the spleen pulp shows a diffuse homogeneous appearance due to a severe loss of lymphoid cells
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• as early as P14, the centers of lymphoid follicles in the white pulp of spleen from mutant mice show reduced cell density
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immune system
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• the thymus appeared histologically normal at P14; however, lymphoid cells were almost entirely absent in the cortex by P25
• stromal cells were prominent and necrotic cell disease was visible in the medulla
• at P14, the number of thymic cells undergoing apoptosis was increased significantly and was further elevated at P25
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• homozygous null mice displayed loss of lymphocytes in the spleen and thymus
|
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• flow cytometric analysis showed that the percentage of CD4+/CD8+ double-positive immature T cells was reduced considerably in P24-P26-day-old affected animals; splenocytes were reduced to a comparable extent at P25 and P26, while the percentage of lymphocytes gated was only moderately reduced and the proportion of IgM/B220+ B cells remained unaffected
|
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• after P16, the cerebral cortex and thalamus of homozygous null mice displayed a significant accumulation of morphologically abnormal microglia, which had expanded and round cell bodies with few thick processes
• by P24, transformed microglia in the cortex and the thalamus displayed enhanced phagocytic activity: they phagocytosed damaged storage neurons laden with ceroid-lipofuscin
• after P20, activated microglia exhibited significant expression of macrophage, inducible nitric oxide synthase-2 (Nos2)
• at P24, homozygotes showed significant accumulation of NO2- (a major metabolite of nitric oxide) and elevated expression of Nos2 in cytosolic fractions of the brain and small intestine
• neither the accumulation of ceroid-lipofuscin in neurons nor the microglial phagocytic activity was affected by chronic treatment of L-NAME or SMT
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• at P25 and P26, the spleen pulp shows a diffuse homogeneous appearance due to a severe loss of lymphoid cells
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• as early as P14, the centers of lymphoid follicles in the white pulp of spleen from mutant mice show reduced cell density
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• analysis of the antigen-presenting properties of cells derived from homozygous null mice, revealed a modest shift in the efficiency of presentation of some antigenic determinants; however, the overall capacity of mutant antigen-presenting cells was unaffected
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vision/eye
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• in the mutant retina, numerous apoptotic (TUNEL-positive) cells were found in the outer nuclear layer (ONL), and to a much lesser extent in the inner nuclear layer (INL)
• nitric oxide synthase was induced in microglial cells, which invaded retinal layers and phagocytosed dead cell debris; NOS inhibitors prevented cell death in the INL, but not in the ONL, indicating that loss of INL neurons is mediated by nitric oxide from microglial cells
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• homozygous null mice displayed progressive degeneration of retinal photoreceptor cells (retinal atrophy)
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nervous system
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• at about P20, homozygous null mice began to display neurological phenotypes with repetitive seizures; they began to tremble and move on their tiptoes with a stiff tail
(J:64892)
• most of L-NAME-treated mutant mice still displayed signs of seizure
(J:71688)
|
|
• in some cases, mutant mice suffered from severe tonic seizures and died as a result of respiratory arrest
|
|
• at the terminal stage, the CNS of homozygous null mice exhibited cell death as shown by the appearance of TUNEL-positive cells, especially in the thalamus
• chronic treatment of L-NAME (a strong competitive NOS inhibitor) or SMT (an Nos2 inhibitor) partially but significantly decreased the number of TUNEL-positive cells in the thalamus at the terminal stage, without affecting the number of TUNEL-positive cells in the dentate gyrus of the hippocampus
|
|
• after P16, the cerebral cortex and thalamus of homozygous null mice displayed a significant accumulation of morphologically abnormal microglia, which had expanded and round cell bodies with few thick processes
• by P24, transformed microglia in the cortex and the thalamus displayed enhanced phagocytic activity: they phagocytosed damaged storage neurons laden with ceroid-lipofuscin
• after P20, activated microglia exhibited significant expression of macrophage, inducible nitric oxide synthase-2 (Nos2)
• at P24, homozygotes showed significant accumulation of NO2- (a major metabolite of nitric oxide) and elevated expression of Nos2 in cytosolic fractions of the brain and small intestine
• neither the accumulation of ceroid-lipofuscin in neurons nor the microglial phagocytic activity was affected by chronic treatment of L-NAME or SMT
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• homozygous null mice displayed progressive degeneration of retinal photoreceptor cells (retinal atrophy)
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homeostasis/metabolism
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• in the final stage of the disease (P25 and P26), mutants showed thromboses of small vessels, which in cardiac muscle concurred with myolysis
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| neuronal ceroid lipofuscinosis 10 | DOID:0110725 |
OMIM:610127 |
J:138648 | |
