Analysis Tools
mortality/aging
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• homozygotes are alive just after delivery but die soon after birth
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craniofacial
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• at E18.5, only a thin layer of fibrous connective tissue is observed between the brain and subcutaneous connective tissue
(J:40783)
• ALP-positive osteoblasts are detected in the fibrous connective tissues, but no calcified bone is observed
(J:40783)
• in addition, no TRAP-positive osteoclasts are present in the calvarial region of mutant embryos (data not shown)
(J:40783)
• at E18.5, mutant calvariae are composed of membranous structures rather than bone tissue as in wild-type mice; ALP-positive areas are confined to the lateral portions
(J:59821)
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growth/size/body
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• at E18.5, the weight of homozygous embryos is ~80% of that of heterozygous and wild-type embryos
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• homozygous mutant embryos and newborns uniformly exhibit dwarfism relative to wild-type counterparts
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• at E18.5, mutant spleens show a 1.5-fold increase in cell number relative to wild-type spleens, indicating splenomegaly
• in addition, mutant splenic vessels appear dilated
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hematopoietic system
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• at E18.5, a few osteoclasts are observed around calcified cartilage in mutant tibias, but they are small and mononuclear, indicating a maturation arrest
(J:40783)
• at E18.5, the TRAP-positive osteoclasts found in the primary spongiosa and periosteum of wild-type tibia are multinuclear; in contrast, those of mutant tibia are primarily mononuclear and are found in the perichondrium at the level of calcified chorndrocytes
(J:59821)
• occasionally, mutant osteoclastic cells have 3 or more nuclei with vacuole-type H+-ATPase immunolocalization and a poorly formed ruffled-border; intracellular polarization remains incomplete
(J:59821)
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• at E18.5, the mutant thymus appears histologically normal
• at E18.5, development of alpha/beta T cells and gamma/delta T cells is normal, although the number of thymocytes is significantly reduced relative to wild-type (data not shown)
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• at E18.5, mutant spleens show a 1.5-fold increase in cell number relative to wild-type spleens, indicating splenomegaly
• in addition, mutant splenic vessels appear dilated
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• homozygotes exhibit a normal number of definitive hematopoietic precursors in yolk sac at E10.5 and liver at E12.5
• at E18.5, mutant livers contain large hematopoietic foci (largely composed of myeloid cells) in the periportal areas, although the number of hematopoietic precursors remains normal, due to increased precursor frequency
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• at E18.5, homozygotes display excessive levels of extramedullary hematopoiesis in both liver and spleen to compensate for absence of bone marrow granulopoiesis
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• at E18.5, homozygotes contain 9x more nucleated cells (primarily nucleated erythrocytes) in peripheral blood smears than wild-type mice
• immature erythroid and myeloid cells are also observed, in the absence of morphological abnormalities
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• at E18.5, mutant livers and spleens contain an increased number of mature granulocytes relative to wild-type, although no significant differences are detected at E17.5
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• at E18.5, the percentage of B220+ B cells are decreased in both mutant livers and spleens
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• no major histological differences are observed in mutant spleens from E15.5-E17.5
• however, at E18.5, mutant spleens contain 2x as many hematopoietic precursors as wild-type spleens
• at this stage, mutant spleen cells are primarily composed of granulocytes
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homeostasis/metabolism
immune system
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• at E18.5, a few osteoclasts are observed around calcified cartilage in mutant tibias, but they are small and mononuclear, indicating a maturation arrest
(J:40783)
• at E18.5, the TRAP-positive osteoclasts found in the primary spongiosa and periosteum of wild-type tibia are multinuclear; in contrast, those of mutant tibia are primarily mononuclear and are found in the perichondrium at the level of calcified chorndrocytes
(J:59821)
• occasionally, mutant osteoclastic cells have 3 or more nuclei with vacuole-type H+-ATPase immunolocalization and a poorly formed ruffled-border; intracellular polarization remains incomplete
(J:59821)
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• at E18.5, the mutant thymus appears histologically normal
• at E18.5, development of alpha/beta T cells and gamma/delta T cells is normal, although the number of thymocytes is significantly reduced relative to wild-type (data not shown)
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• at E18.5, mutant spleens show a 1.5-fold increase in cell number relative to wild-type spleens, indicating splenomegaly
• in addition, mutant splenic vessels appear dilated
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• at E18.5, mutant livers and spleens contain an increased number of mature granulocytes relative to wild-type, although no significant differences are detected at E17.5
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• at E18.5, the percentage of B220+ B cells are decreased in both mutant livers and spleens
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• no major histological differences are observed in mutant spleens from E15.5-E17.5
• however, at E18.5, mutant spleens contain 2x as many hematopoietic precursors as wild-type spleens
• at this stage, mutant spleen cells are primarily composed of granulocytes
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limbs/digits/tail
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• at E18.5, mutant femurs are composed of non-calcified cartilage; neither ALP-positive nor TRAP-positive cells are found in the perichondrium of mutant femurs (data not shown)
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• at E18.5, the middle part of tibia remains as calcified cartilage without formation of the bone-marrow cavity; neither vascular nor mesenchymal cell invasion is detected in the calcified cartilage
(J:40783)
• ALP-positive osteoblasts are found in the perichondrial region of calcified cartilage but no bone is formed
(J:40783)
• a few TRAP-positive osteoclasts appear adjacent to the calcified cartilage at the perichondrium; however, the size of cells and the number of nuclei are reduced relative to wild-type
(J:40783)
• at E18.5, mutant tibiae are smaller and thinner and consist of calcified cartilage and ALP-positive perichondrium
(J:59821)
• in mutant tibiae, most ALP-positive perichondrial cells have a spindle-shaped cell contour and reduced cytoplasm, the extracellular matrix of which lacks both type I collagen and calcifying matrix vesicles
(J:59821)
• notably, some perichondrial cells at the very middle part of mutant tibiae become flattened; a thin layer of type I collagen-based calcified matrix is found near these cells
(J:59821)
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• at E18.5, mutant tibiae are smaller and thinner
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short limbs
(
J:40783
)
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• at E18.5, mutant embryos have shorter legs than wild-type embryos
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liver/biliary system
small liver
(
J:53069
)
|
• at E18.5, mutant livers appear grossly smaller than wild-type livers
• however, no major histological differences are observed in mutant livers from E15.5-E17.5
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• at E18.5, the total cell number of mutant livers is reduced to ~50% of wild-type cell number
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muscle
| N |
• at E18.5, homozygotes display normal tendon histology relative to wild-type embryos
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respiratory system
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• soon after birth, homozygotes exhibit respiratory failure due to the absence of rib ossification
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skeleton
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• at E18.5, only a thin layer of fibrous connective tissue is observed between the brain and subcutaneous connective tissue
(J:40783)
• ALP-positive osteoblasts are detected in the fibrous connective tissues, but no calcified bone is observed
(J:40783)
• in addition, no TRAP-positive osteoclasts are present in the calvarial region of mutant embryos (data not shown)
(J:40783)
• at E18.5, mutant calvariae are composed of membranous structures rather than bone tissue as in wild-type mice; ALP-positive areas are confined to the lateral portions
(J:59821)
|
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• at E18.5, mutant femurs are composed of non-calcified cartilage; neither ALP-positive nor TRAP-positive cells are found in the perichondrium of mutant femurs (data not shown)
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• at E18.5, the middle part of tibia remains as calcified cartilage without formation of the bone-marrow cavity; neither vascular nor mesenchymal cell invasion is detected in the calcified cartilage
(J:40783)
• ALP-positive osteoblasts are found in the perichondrial region of calcified cartilage but no bone is formed
(J:40783)
• a few TRAP-positive osteoclasts appear adjacent to the calcified cartilage at the perichondrium; however, the size of cells and the number of nuclei are reduced relative to wild-type
(J:40783)
• at E18.5, mutant tibiae are smaller and thinner and consist of calcified cartilage and ALP-positive perichondrium
(J:59821)
• in mutant tibiae, most ALP-positive perichondrial cells have a spindle-shaped cell contour and reduced cytoplasm, the extracellular matrix of which lacks both type I collagen and calcifying matrix vesicles
(J:59821)
• notably, some perichondrial cells at the very middle part of mutant tibiae become flattened; a thin layer of type I collagen-based calcified matrix is found near these cells
(J:59821)
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• at E18.5, mutant tibiae are smaller and thinner
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• at E18.5, mutant tibia show absence of a bone marrow cavity
(J:40783)
• at E18.5, homozygotes present a congenital loss of bone marrow throughout the entire skeleton; no hematopoietic cells are obtained from mutant femur, tibia or fibula
(J:53069)
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• in E18.5 homozygous tibiae, hypertrophic chondrocytes display irregular alignment
• as cartilaginous calcification progresses, hypertrophic chondrocytes become flattened and show low electron density in the cytoplasm as well as irregularly shaped nuclei
• however, once deeply embedded in calcified matrix, mutant chondrocytes become smaller, with round or oval nuclei and abundant organelles; lamina limitans is well-developed
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• at E15.5-E16.5, mutant embryos display an absence of calcification throughout the body, unlike wild-type embryos, which show well-calcified skeletons; in contrast, cartilage development remains unaffected
• at E18.5, the entire skeleton is composed of cartilage, with no vascular or mesenchymal cell invasion within the cartilage, and no hematopoietic precursors associated with bone structures throughout the entire skeleton
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• homozygotes exhibit a maturational arrest at an early stage of osteoblast differentiation
(J:40783)
• at E18.5, osteoblasts in mutant radiuses are flat and observed only in the perichondrial region
(J:40783)
• in E18.5 homozygotes, osteoblastic cells show ALP activity; however, most of them neither produce type I collagen or noncollagenous bone matrix proteins nor form calcified bone matrix
(J:59821)
• mutant perichondrial cells possess small cytoplasms and poorly developed cell organelles
(J:59821)
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• at E18.5, a few osteoclasts are observed around calcified cartilage in mutant tibias, but they are small and mononuclear, indicating a maturation arrest
(J:40783)
• at E18.5, the TRAP-positive osteoclasts found in the primary spongiosa and periosteum of wild-type tibia are multinuclear; in contrast, those of mutant tibia are primarily mononuclear and are found in the perichondrium at the level of calcified chorndrocytes
(J:59821)
• occasionally, mutant osteoclastic cells have 3 or more nuclei with vacuole-type H+-ATPase immunolocalization and a poorly formed ruffled-border; intracellular polarization remains incomplete
(J:59821)
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• in mutant proximal limbs, the growth plates do not even form the columnar zone of proliferating cells
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• the calcification normally observed in the region of finally differentiated hypertrophied chondrocytes is only detected in restricted parts of mutant cartilage, suggesting that the final differentiation of chondrocytes is impaired
(J:40783)
• mutant chondrocytes differentiate to hypertrophic chondrocytes only in restricted parts of the skeleton, including the tibia, fibula, radius, and ulna (where cartilage calcification occurs in the absence of vascular invasion)
(J:54095)
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• in E18.5 homozygous tibiae, the zone of proliferative chondrocytes appears more narrow (hypoplastic) than normal
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• in mutant distal limbs, the zone of proliferating chondrocytes is narrow and that of hypertrophic chondrocytes is wide relative to wild-type
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• homozygotes show a mild blockage of chondrocyte differentiation in distal limbs (tibia, fibula, radius, and ulna)
• in contrast, chondrocyte differentiation is severely perturbed prior to the maturational stage of prehypertrophic chondrocytes in other skeletal parts, including proximal limbs (humerus and femur), ribs, vertebrae, manus, pedes, and craniofacial region
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• homozygotes show complete inhibition of intramembranous and endochondral ossification due to a maturational block of osteoblasts
(J:40783)
• at E18.5, both endochondral and intramembranous ossification are arrested
(J:59821)
|
nervous system
| N |
• no abnormal central nervous system phenotypes detected
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integument
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• in the mutant dermis, fibroblasts appear to be slightly reduced in number; however, dermal thickness remains relatively unaffected (data not shown)
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cellular
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• homozygotes exhibit a maturational arrest at an early stage of osteoblast differentiation
(J:40783)
• at E18.5, osteoblasts in mutant radiuses are flat and observed only in the perichondrial region
(J:40783)
• in E18.5 homozygotes, osteoblastic cells show ALP activity; however, most of them neither produce type I collagen or noncollagenous bone matrix proteins nor form calcified bone matrix
(J:59821)
• mutant perichondrial cells possess small cytoplasms and poorly developed cell organelles
(J:59821)
|
|
• at E18.5, a few osteoclasts are observed around calcified cartilage in mutant tibias, but they are small and mononuclear, indicating a maturation arrest
(J:40783)
• at E18.5, the TRAP-positive osteoclasts found in the primary spongiosa and periosteum of wild-type tibia are multinuclear; in contrast, those of mutant tibia are primarily mononuclear and are found in the perichondrium at the level of calcified chorndrocytes
(J:59821)
• occasionally, mutant osteoclastic cells have 3 or more nuclei with vacuole-type H+-ATPase immunolocalization and a poorly formed ruffled-border; intracellular polarization remains incomplete
(J:59821)
|
endocrine/exocrine glands
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• at E18.5, the mutant thymus appears histologically normal
• at E18.5, development of alpha/beta T cells and gamma/delta T cells is normal, although the number of thymocytes is significantly reduced relative to wild-type (data not shown)
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| cleidocranial dysplasia | DOID:13994 |
OMIM:119600 OMIM:216330 |
J:40783 , J:53069 , J:54095 | |
