Analysis Tools
mortality/aging
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• mutant mice die at birth, indicating partial rescue of the embryonic lethality observed in Rb1tm1Tyj homozygotes at E13.5-E14.5
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muscle
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• at E16.5-P0, mutant mice display abnormal myogenesis, with shorter myotubes relative to control mice
• strikingly, when present, mutant myotubes are widely dispersed, and contain enlarged nuclei that are 2-4 times longer than normal
• the number of elongated nuclei increases with time, approaching ~2% and >10% of the myotomal nuclei at E17.5 and E18.5, respectively
• at E17.5, BrdU staining indicates that mutant giant nuclei continue to actively synthesize DNA within myotubes, at a stage when DNA synthesis would have normally ceased
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• at E16.5-E18.5, TUNEL analysis indicates a significant increase of apoptotic nuclei in mutant skeletal muscles prior to myoblast fusion
• in contrast, no significant increase in apoptosis is noted in mutant cardiac muscles
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• at E17.5, the myofibrils of mutant limb and tongue muscles are shorter and less abundant, although individual sarcomeric units appear intact
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• at birth, mutants exhibit reduced skeletal muscle mass
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• at E16.5-P0, mutant mice display reduced muscle fiber density in axial, tongue, and limb muscles
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behavior/neurological
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• at E16.5 and P0, mutants display a typical hunchback posture
• however, in contrast to Rb1tm1Tyj homozygotes, the perichondrium appears normal at E13.5
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• at birth, mutants fail to move
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skeleton
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• at E18.5, mutant mice lack a normal cervical curvature
• however, bones are present and normal in shape
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vision/eye
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• at birth, mutant mice exhibit impaired lens development
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• at E17.5-P0, mutant mice display significant degeneration of the lens fibers
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cellular
polyploidy
(
J:98518
)
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• in addition to aberrant cochlear and vestibular hair cell proliferation, E18.5 mutant mice exhibit multinucleated and enlarged hair cells in the inner ear sensory epithelia
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• unlike control mice where cells of the organ of Corti and almost all cells of the greater epithelial ridge are postmitotic at E18.5, mutants show ectopic mitoses in the greater epithelial ridge and the region of cochlear inner and outer HCs
• in addition, high numbers of mitotic vestibular hair cells are detected in mutant utricular, saccular, and ampullary sensory epithelia
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• at E17.5 and E18.5, supernumerary cochlear and vestibular HC production is partially compensated by increased apoptosis in mutant inner ear sensory epithelia
(J:98518)
• at E16.5-E18.5, TUNEL analysis indicates a significant increase in apoptotic nuclei in mutant axial and tongue muscles
(J:37145)
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hematopoietic system
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• in contrast to Rb1tm1Tyj homozygotes which fail to undergo enucleation of red blood cells, partially rescued mutant mice display only a slight delay in enucleation, with ~2-4% nucleated red blood cells present at E18.5
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nervous system
| N |
• at E17.5-P0, mutant mice show a near normal neurogenesis, as shown by normal expression of neuronal markers in brain, trigeminal ganglia, retina, motor neurons, and dorsal root ganglia
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• at E17.5 and E18.5, mutant mice exhibit excessive proliferation of differentiating cochlear HCs
• at E18.5, the upper basal turn of mutant cochleas shows a 6-fold increase in the numbers of HC nuclei relative to controls
• at birth, mutants display ectopic mitoses in the greater epithelial ridge and the region of cochlear IHCs and OHCs, not present in control mice
• most mitotic cochlear HCs are located near the lumen, while some are found in deeper epithelial layers
• increased mitotic activity and overproduction of cochlear HCs is first evident at E15.5
• at E17.5 and E18.5, supernumerary cochlear HC production is partially compensated by increased apoptosis
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• at E18.5, mutant IHCs are actively cycling, displaying a rounded morphology, typical of dividing cells
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• at E18.5, mutant OHCs are actively cycling, displaying a rounded morphology, typical of dividing cells
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• at E17.5 and E18.5, mutants exhibit a hyperplastic vestibular sensory epithelium due to overproduction of HCs
• HCs are abnormally intermixed with supporting cells in the middle layers while the basal part of the epithelium is filled with supernumerary HCs
• some vestibular HCs are mislocated through the basal lamina into the mesenchyme
• a distinct pathology, including multinucleated and enlarged HCs, apoptosis, and infiltration of HCs into the mesenchyme is observed
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• at E17.5 and E18.5, mutant mice exhibit excessive proliferation of differentiating vestibular HCs
• at E18.5, mutant vestibular HCs are actively cycling, displaying a rounded morphology, typical of dividing cells
• most mitotic vestibular HCs are located at the lumenal surface, but some are found in deeper epithelial levels and in mesenchyme
• increased mitotic activity and overproduction of vestibular HCs is first evident at E14.5
• at E17.5 and E18.5, supernumerary vestibular HC production is partially compensated by increased apoptosis
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• at birth, mutants display abnormal stereociliary bundle morphologies, particularly in the utricle
• supernumerary vestibular HCs in the deeper epithelial layers and in mesenchyme exhibit disorganized cilia-like protusions and loss of the apicobasal polarity
• however, near-normal stereociliary bundles are also observed, often in ampullae
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hearing/vestibular/ear
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• at E17.5 and E18.5, mutant mice exhibit a thickened greater epithelial ridge and a hyperplastic organ of Corti due to excessive hair cell (HC) formation, esp. in the basal half of the cochlea
• however, mutant cochlear HCs exhibit a normal profile of molecules involved in differentiation and maturation
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• at E17.5 and E18.5, mutant mice exhibit excessive proliferation of differentiating cochlear HCs
• at E18.5, the upper basal turn of mutant cochleas shows a 6-fold increase in the numbers of HC nuclei relative to controls
• at birth, mutants display ectopic mitoses in the greater epithelial ridge and the region of cochlear IHCs and OHCs, not present in control mice
• most mitotic cochlear HCs are located near the lumen, while some are found in deeper epithelial layers
• increased mitotic activity and overproduction of cochlear HCs is first evident at E15.5
• at E17.5 and E18.5, supernumerary cochlear HC production is partially compensated by increased apoptosis
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• at E18.5, mutant IHCs are actively cycling, displaying a rounded morphology, typical of dividing cells
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• at E18.5, mutant OHCs are actively cycling, displaying a rounded morphology, typical of dividing cells
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• at E17.5 and E18.5, supporting cell numbers are increased, but not to the extent of HC overproduction
• at E18.5, the upper basal turn of mutant cochleas shows a 3-fold increase in the numbers of Deiters' plus pillar cells found below HCs relative to controls
• however, no ectopic mitoses are detected in the mutant supporting cell layer
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• at E17.5 and E18.5, mutants exhibit a hyperplastic vestibular sensory epithelium due to overproduction of HCs
• HCs are abnormally intermixed with supporting cells in the middle layers while the basal part of the epithelium is filled with supernumerary HCs
• some vestibular HCs are mislocated through the basal lamina into the mesenchyme
• a distinct pathology, including multinucleated and enlarged HCs, apoptosis, and infiltration of HCs into the mesenchyme is observed
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• at E17.5 and E18.5, mutant mice exhibit excessive proliferation of differentiating vestibular HCs
• at E18.5, mutant vestibular HCs are actively cycling, displaying a rounded morphology, typical of dividing cells
• most mitotic vestibular HCs are located at the lumenal surface, but some are found in deeper epithelial levels and in mesenchyme
• increased mitotic activity and overproduction of vestibular HCs is first evident at E14.5
• at E17.5 and E18.5, supernumerary vestibular HC production is partially compensated by increased apoptosis
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• at birth, mutants display abnormal stereociliary bundle morphologies, particularly in the utricle
• supernumerary vestibular HCs in the deeper epithelial layers and in mesenchyme exhibit disorganized cilia-like protusions and loss of the apicobasal polarity
• however, near-normal stereociliary bundles are also observed, often in ampullae
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• at birth, the mutant utricular sensory epithelium is hyperplastic due to an excess of HCs, some of which have penetrated into the mesenchyme
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