Analysis Tools
mortality/aging
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• homozygotes die within minutes of birth due to respiratory failure caused by skeletal defects
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skeleton
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• homozygotes exhibit endochondral defects throughout the appendicular skeleton
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• at birth, homozygotes display kinks in the radius, ulna, tibia and fibula
• at E14.5, mutant long bones are already bent near the junction between hypertrophic and nonhypertrophic cells
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bowed radius
(
J:83260
)
bowed ulna
(
J:83260
)
bowed fibula
(
J:83260
)
bowed tibia
(
J:83260
)
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• at E16.5, the junction between the zones occupied by prehypertrophic and hypertrophic chondrocytes is disorganized in mutant radii
• at P0, longitudinal columns appear disorganized within the hypertrophic zones of mutant femora
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• at E16.5, the growth plates of mutant radii are expanded
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• homozygotes display axial defects along the entire vertebral column
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• newborn homozygotes lack ethmoid bones
• however, no obvious defects in other membrane bones, such as the occipital bone, are observed
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• newborn homozygotes display shortened mandibles
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domed cranium
(
J:83260
)
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• newborn homozygotes display a domed skull
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• neonatal mutant rib cages exhibit deformed cartilage and kinked ribs
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• ~10% of homozygotes display misaligned sternal fusion
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short sternum
(
J:83260
)
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• neonatal mutant sterna are short
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• at birth, ossified regions of the mutant ribs are kinked due to prior defects in chondrogenesis
• however, the overall lengths of individual ribs are not significantly altered
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• at E14.5 and P0, mutant vertebrae are broader than wild-type
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• at E14.5 and P0, mutant atlases are broader than wild-type
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• homozygotes are osteopenic; the amount of mineralization is significantly reduced, as shown by von Kossa-staining of neonatal femora
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• consistent with a defect in growth plate angiogenesis, the bone collar adjacent to the expanded hypertrophic chondrocyte zone is thinner, and less trabecular bone is observed
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• at E14.5, the mutant rib cartilage adjacent to sites of mineralization is already bent; the extent of ossification is reduced while the zone of mineralizing cartilage is expanded leading to kinked ribs at birth
• by E13.5, the mutant limb cartilage is also deformed leading to kinks in the long bones at birth
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• newborn homozygotes display a deformed Meckel's cartilage
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• at E15.5 and P0, all homozygotes exhibit deformed nasal cartilage
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• homozygotes show multiple defects in chondrogenesis, including impaired chondrocyte proliferation, defects in extracellular matrix remodeling, and impaired growth plate angiogenesis associated with an enlarged zone of hypertrophy, decreased levels of VEGF expression in hypertrophic cartilage, and reduced recruitment of MMP9-expressing chondroclasts/osteoclasts to the growth plate
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• at P0, homozygotes display reduced expression levels of specific extracellular matrix components (aggrecan and link protein) within the hypertrophic zone, leading to inferior cartilage mechanical properties
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• at E16.5, mutant long bones exhibit an enlarged and disorganized hypertrophic zone that persists until birth
• at P0, mutant mineralized bone collars are lengthened and thinner than wild-type, consistent with an expanded hypertrophic zone
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• homozygotes exhibit generalized chondrodysplasia
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• homozygotes display defective replacement of cartilage by bone during endochondral ossification
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• at E14.5, but not at E12.5, homozygotes display reduced rates of chondrocyte cell proliferation, as detected by PCNA staining; this proliferative defect is more pronounced at E16.5
• however, no altered rates of chondrocyte apoptosis are observed
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respiratory system
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• at E15.5 and P0, all homozygotes exhibit deformed nasal cartilage
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• at E18.5, mutant lungs appear to be arrested at the canalicular stage of lung development
• immunostaining for PDGFB, its receptor and IGF1, are markedly attenuated, while the normal proximal-to-distal increasing TTF1 gradient is lost, indicating abnormal distribution and abundance of cell cycle modulators involved in lung development
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• lung cell proliferation is significantly reduced in the mesenchymal cell compartment
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• at E18.5, mutant lungs show lack of expanded saccules
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small lung
(
J:130165
)
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• at E18.5, mutant fetal lungs are significantly smaller wild-type lungs
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• at E18.5, the average weight of mutant fetal lungs is significantly lower than that of wild-type lungs
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• at E18.5, features of lung hypoplasia, including dense cellularity, thicker septae, and absence of expanded saccules are observed
• lung cell proliferation is significantly reduced in both the epithelial and the mesenchymal cell compartments
• in contrast, apoptotic cell death is significantly increased in both the epithelial and the mesenchymal lung compartments
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• at E18.5, the potential alveolar airspace is significantly reduced
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• at E18.5, the proportion of PAS+ epithelial cells, indicating cytoplasmic glycogen, is 4x higher than that in wild-type fetal lungs, suggesting impaired maturation of type II pneumocytes
• mutant type II cells exhibit smaller nuclei and large cytoplasmic accumulations of glycogen, indicating limited surfactant synthesis
• however, epithelial cell immunostaining for surfactant-associated protein-C (SP-C) is normal
• type I pneumocyte differentiation is not affected
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• at E18.5, mutant cytoplasmic lamellar bodies are smaller in size, though their structure and number is similar to than in wild-type controls
• released (intra-alveolar) lamellar bodies and tubular myelins appear morphologically normal
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• at E18.5, mutant lung airspaces appear as narrow and tortuous tubules
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• neonatal homozygotes exhibit respiratory failure caused by skeletal defects
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cardiovascular system
| N |
• no defects in general angiogenesis or impaired cardiac function are observed
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• neonatal homozygotes display impaired growth plate angiogenesis leading to expanded hypertrophic chondrocyte zones
• only a few capillaries invade the cartilage matrix at the ossification zone, although blood vessels are observed within intertrabecular spaces of the metaphysis
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limbs/digits/tail
bowed radius
(
J:83260
)
bowed ulna
(
J:83260
)
bowed fibula
(
J:83260
)
bowed tibia
(
J:83260
)
craniofacial
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• newborn homozygotes display a deformed Meckel's cartilage
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• newborn homozygotes lack ethmoid bones
• however, no obvious defects in other membrane bones, such as the occipital bone, are observed
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• newborn homozygotes display shortened mandibles
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domed cranium
(
J:83260
)
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• newborn homozygotes display a domed skull
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• at E15.5 and P0, all homozygotes exhibit a secondary cleft palate
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• all newborn homozygotes show a failure in elevation of the palatal shelves
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• at E15.5 and P0, all homozygotes exhibit deformed nasal cartilage
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digestive/alimentary system
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• at E15.5 and P0, all homozygotes exhibit a secondary cleft palate
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• all newborn homozygotes show a failure in elevation of the palatal shelves
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growth/size/body
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• at E15.5 and P0, all homozygotes exhibit a secondary cleft palate
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• all newborn homozygotes show a failure in elevation of the palatal shelves
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• at E15.5 and P0, all homozygotes exhibit deformed nasal cartilage
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• a visibly reduced thoracic volume is observed
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• neonatal mutant sterna are bent inwards
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cellular
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• lung cell proliferation is significantly reduced in the mesenchymal cell compartment
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