Analysis Tools
growth/size/body
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• although body weight is normal at P2, mice show a significant reduction in average weight by 1-2 months of age
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microcephaly
(
J:224364
)
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• mice exhibit microcephaly at P2
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nervous system
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• increased cell death throughout the developing cortex at E14.5, as shown by increased cleaved caspase-3 staining and TUNEL staining
• cell death is triggered by centrosome-based mitotic errors
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• slightly increased numbers of mitotic (p-H3Ser10-positive) cells in the ventricular zone (VZ) of the developing cortex at E14.5
• strong p53 staining in the proliferating cell nuclear antigen (PCNA)-positive cells of the VZ at E14.5
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• forebrain size is reduced at P2
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• cerebral cortex size is reduced at P2
• no CEP152 or CEP63 localization to centrosomes is detected in the developing cortex at E14.5, unlike in wild-type controls, indicating defective CEP63/CEP152 centrosomal recruitment
• increased number and defective localization of mitotic (p-H3Ser10-poistive) cells is noted at E14.5
• misplaced mitotic cells are both Tbr2-positive and -negative cells, suggesting that displaced population contains both intermediate progenitors and radial glial cell progenitors
• increased cell death in the cortex at E14.5, as shown by increased cleaved caspase-3 staining and TUNEL staining
• striking upregulation of p53 in the cortex at E14.5
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• at P2, cortices show a significant reduction in thickness at all positions examined (motor, visual, and somatosensory)
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• reduced total number of SOX2-positive neural progenitor cells (NPCs) in the cortex at E14.5, with concomitant increase in the percentage of mislocalized NPCs
• attrition of NPCs involves p53-dependent cell death
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reproductive system
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• reduction in oocyte number, although follicles are present at all stages
• however, females are fertile and produce normal litter sizes
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• occasional spermatagonia exhibit tetraploidy
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• abnormal synaptonemal complex (SC) structures are observed in zygotene and pachytene spermatocytes, including SC entanglements, chromosome fusions, and ring gamma-H2AX staining indicative of programmed cell death
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• increased cell death in seminiferous tubules, as shown by TUNEL staining
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• decreased seminiferous tubule diameter and cellularity at P60
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• severe defects in testes development
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small testis
(
J:224364
)
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• progressive reduction in testis size starting at P10
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• progressive reduction in testis weight, first evident at P10 and more obvious at P60 and P165
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• reduced cellularity in seminiferous tubules but proportionally normal numbers of spermatagonia at P5
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• spermatogenesis is impaired at multiple stages
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azoospermia
(
J:224364
)
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• no identifiable sperm in the vas deferens, indicating that rare spermatids do not leave the testes
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• only a few spermatids are observed in testes sections
• rare elongated spermatids identified in testes squash preparations appear morphologically abnormal, in some cases showing DNA compaction defects
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• CEP63 and CEP152 are not detected at centrosomes (marked by PCNT) in SCP3-staged prophase I spermatocytes, unlike in wild-type cells
• spermatocytes show numerical and structural centrosome aberrations, chromosome entanglements, and defective telomere clustering
• most spermatocyte centrosomes show abnormal pericentriolar material organization, with a hollow central region and an increase in extrusion number
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• quantification of prophase I stages in meiotic cells showed increased leptotene and zygotene stage cells, normal numbers of pachytene cells but very few cells (4%) progressing to diplotene, indicating a defect in meiotic prophase I progression
• increased numbers of foci of the RAD51 and DMC1 repair proteins are observed from leptotene to zygotene, suggesting that resolution of double-strand breaks (DSBs) may be impaired
• many pachytene and diplotene cells show diffuse gamma-H2AX staining that is not restricted to the sex-body, consistent with delayed repair
• most pachytene cells lack detectable MLH1 foci (marker of crossover formation), indicating that they fail to progress past early pachytene
• when MLH1 foci are present, higher numbers of crossovers per autosome and longer synaptonemal complexes are observed
• many spermatocytes have only one or no detectable centriole at leptotene, and most existing centrioles fail to duplicate during prophase I; as a result, by pachytene/diplotene, spermatocytes contain on average only two centrioles, whereas wild-type cells contain four
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• males are infertile, despite normal copulation
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cellular
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• reduction in oocyte number, although follicles are present at all stages
• however, females are fertile and produce normal litter sizes
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azoospermia
(
J:224364
)
|
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• no identifiable sperm in the vas deferens, indicating that rare spermatids do not leave the testes
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• only a few spermatids are observed in testes sections
• rare elongated spermatids identified in testes squash preparations appear morphologically abnormal, in some cases showing DNA compaction defects
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• CEP63 and CEP152 are not detected at centrosomes (marked by PCNT) in SCP3-staged prophase I spermatocytes, unlike in wild-type cells
• spermatocytes show numerical and structural centrosome aberrations, chromosome entanglements, and defective telomere clustering
• most spermatocyte centrosomes show abnormal pericentriolar material organization, with a hollow central region and an increase in extrusion number
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• occasional spermatagonia exhibit tetraploidy
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polyploidy
(
J:224364
)
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• occasional polyploid spermatagonia are observed in testes squash preparations
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• at P10, males show a significant reduction of telomere clustering in spermatocytes
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• quantification of prophase I stages in meiotic cells showed increased leptotene and zygotene stage cells, normal numbers of pachytene cells but very few cells (4%) progressing to diplotene, indicating a defect in meiotic prophase I progression
• increased numbers of foci of the RAD51 and DMC1 repair proteins are observed from leptotene to zygotene, suggesting that resolution of double-strand breaks (DSBs) may be impaired
• many pachytene and diplotene cells show diffuse gamma-H2AX staining that is not restricted to the sex-body, consistent with delayed repair
• most pachytene cells lack detectable MLH1 foci (marker of crossover formation), indicating that they fail to progress past early pachytene
• when MLH1 foci are present, higher numbers of crossovers per autosome and longer synaptonemal complexes are observed
• many spermatocytes have only one or no detectable centriole at leptotene, and most existing centrioles fail to duplicate during prophase I; as a result, by pachytene/diplotene, spermatocytes contain on average only two centrioles, whereas wild-type cells contain four
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• abnormal synaptonemal complex (SC) structures are observed in zygotene and pachytene spermatocytes, including SC entanglements, chromosome fusions, and ring gamma-H2AX staining indicative of programmed cell death
|
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• increased number and defective localization of mitotic (p-H3Ser10-poistive) cells in the developing cortex at E14.5
• misplaced mitotic cells are both Tbr2-positive and -negative cells suggesting that displaced population contains both intermediate progenitors and radial glial cell progenitors
• slightly increased numbers of mitotic (p-H3Ser10-positive) cells in the ventricular zone (VZ) of the developing cortex at E14.5
• increased number of extra-VZ p-H3Ser10-positive cells in the cortex at E14.5
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• increase in the percentage of monopolar spindle configurations in the ventricular zone of the developing cortex at E14.5
• cells with bipolar spindles frequently show dim or absent gamma-tubulin (centrosome) staining at one of the poles, suggesting that spindle poles are formed by defective centrosomes or are acentrosomal
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• increased cell death throughout the developing cortex at E14.5, as shown by increased cleaved caspase-3 staining and TUNEL staining
• cell death is triggered by centrosome-based mitotic errors
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|
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• increased cell death in seminiferous tubules, as shown by TUNEL staining
|
|
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• increased numbers of foci of the RAD51 and DMC1 repair proteins are observed in spermatocytes from leptotene to zygotene, suggesting that resolution of DSBs may be impaired
• many pachytene and diplotene cells show diffuse gamma-H2AX staining that is not restricted to the sex-body, consistent with delayed repair
• however, DNA damage responses are largely normal in cultured mouse embryonic fibroblasts as well as in mice during immune system development
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endocrine/exocrine glands
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• increased cell death in seminiferous tubules, as shown by TUNEL staining
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• decreased seminiferous tubule diameter and cellularity at P60
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• severe defects in testes development
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small testis
(
J:224364
)
|
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• progressive reduction in testis size starting at P10
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• progressive reduction in testis weight, first evident at P10 and more obvious at P60 and P165
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• reduced cellularity in seminiferous tubules but proportionally normal numbers of spermatagonia at P5
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homeostasis/metabolism
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• increased numbers of foci of the RAD51 and DMC1 repair proteins are observed in spermatocytes from leptotene to zygotene, suggesting that resolution of DSBs may be impaired
• many pachytene and diplotene cells show diffuse gamma-H2AX staining that is not restricted to the sex-body, consistent with delayed repair
• however, DNA damage responses are largely normal in cultured mouse embryonic fibroblasts as well as in mice during immune system development
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behavior/neurological
| N |
• despite reduced cortex size, aging mice show no obvious motor defects
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Seckel syndrome | DOID:0050569 |
OMIM:PS210600 |
J:224364 | |
