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Phenotypes Associated with This Genotype
Genotype
MGI:5819194
Allelic
Composition
Cep63Gt(EUCE0251h11)Hmgu/Cep63Gt(EUCE0251h11)Hmgu
Genetic
Background
involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6
Find Mice Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Cep63Gt(EUCE0251h11)Hmgu mutation (0 available); any Cep63 mutation (33 available)
phenotype observed in females
phenotype observed in males
N normal phenotype
growth/size/body
• although body weight is normal at P2, mice show a significant reduction in average weight by 1-2 months of age
• mice exhibit microcephaly at P2

nervous system
• 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
• 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
• forebrain size is reduced at P2
• 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
• at P2, cortices show a significant reduction in thickness at all positions examined (motor, visual, and somatosensory)
• 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

reproductive system
• reduction in oocyte number, although follicles are present at all stages
• however, females are fertile and produce normal litter sizes
• occasional spermatagonia exhibit tetraploidy
• increased cell death in seminiferous tubules, as shown by TUNEL staining
• decreased seminiferous tubule diameter and cellularity at P60
• severe defects in testes development
• progressive reduction in testis size starting at P10
• progressive reduction in testis weight, first evident at P10 and more obvious at P60 and P165
• reduced cellularity in seminiferous tubules but proportionally normal numbers of spermatagonia at P5
• 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
• spermatogenesis is impaired at multiple stages
• no identifiable sperm in the vas deferens, indicating that rare spermatids do not leave the testes
• 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
• 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
• 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
• males are infertile, despite normal copulation

cellular
• at P10, males show a significant reduction of telomere clustering in spermatocytes
• occasional polyploid spermatagonia are observed in testes squash preparations
• reduction in oocyte number, although follicles are present at all stages
• however, females are fertile and produce normal litter sizes
• no identifiable sperm in the vas deferens, indicating that rare spermatids do not leave the testes
• 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
• 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
• occasional spermatagonia exhibit tetraploidy
• 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
• 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
• 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
• 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
• increased cell death in seminiferous tubules, as shown by TUNEL staining

endocrine/exocrine glands
• increased cell death in seminiferous tubules, as shown by TUNEL staining
• decreased seminiferous tubule diameter and cellularity at P60
• severe defects in testes development
• progressive reduction in testis size starting at P10
• progressive reduction in testis weight, first evident at P10 and more obvious at P60 and P165
• reduced cellularity in seminiferous tubules but proportionally normal numbers of spermatagonia at P5

homeostasis/metabolism
• 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

behavior/neurological
N
• despite reduced cortex size, aging mice show no obvious motor defects

Mouse Models of Human Disease
DO ID OMIM ID(s) Ref(s)
Seckel syndrome DOID:0050569 OMIM:PS210600
J:224364


Contributing Projects:
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB), Gene Ontology (GO)
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last database update
03/31/2020
MGI 6.15
The Jackson Laboratory