Analysis Tools
growth/size/body
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• homozygotes are healthy but slightly smaller (80% of wild-type body weight)
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endocrine/exocrine glands
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• homozygotes exhibit impairment of postnatal pancreatic beta cell generation
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• at P30, the percentage of pancreatic alpha cells is increased in mutant islets relative to wild-type islets
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• at P30, the actual beta cell mass is ~24-30% that of wild-type mice
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• at P30, the number of beta cells in individual mutant islets is ~40-50% that of wild-type mice
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• at P30, the total islet number is ~60% that of wild-type mice
• at P30, the number of larger islets is significantly reduced in the mutant pancreas
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• mutant pancreatic beta cells show a decrease in Ca2+ channel activity at the lower range of membrane potentials (at -10 mV and -20 mV) relative to wild-type beta cells
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• BrdU-labeling indicates a significant reduction in the proliferation rate of mutant beta cells at P14 and P30
• however, no increase in cell death of mutant islets is observed at these stages
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• in culture, isolated mutant islets secrete less insulin than wild-type islets at 3 mM ambient glucose
• however, no significant difference in insulin secretion are noted at glucose concentrations of 6 mM or higher
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homeostasis/metabolism
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• in culture, isolated mutant islets secrete less insulin than wild-type islets at 3 mM ambient glucose
• however, no significant difference in insulin secretion are noted at glucose concentrations of 6 mM or higher
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• at 10 weeks of age, nonfasting homozygotes exhibit significantly lower serum insulin levels than wild-type mice
• after overnight fasting (i.e., before glucose injection), most homozygotes display serum insulin levels less than 0.1 ng/ml relative to 0.24 0.06 ng/ml in wild-type mice
• at 30 minutes after glucose injection, mutant serum insulin levels remain below 0.1 ng/ml, whereas wild-type serum insulin levels increase by 2-fold
• however, homozygotes exhibit normoglycemia in fed states and do not develop diabetes over the 1-year observation period
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• at 12-14 weeks, female homozygotes remain hyperglycemic 2 hrs after i.p. injection of glucose, whereas blood glucose levels return to baseline levels in wild-type mice
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• adult homozygotes injected with 0.75 IU/kg body weight human insulin display a significant lowering of blood glucose levels relative to wild-type mice
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• electrophysiological data indicate that the calcium current density at -10 mV and -20 mV is reduced by ~50% and ~70% in mutant beta pancreatic cells, respectively, relative to wild-type
• at potentials of 10 mV or above, the maximal calcium current density is restored to normal levels, due to the compensatory overexpression of another L-type channel (alpha-1C) in mutant beta cells both in adulthood and at P14
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behavior/neurological
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• homozygotes lack a motor reflex in response to an auditory stimulus
(J:72316)
• however, homozygotes display a normal swimming performance as well as normal balance on both a stationary and a rotating cylinder
(J:118306)
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hearing/vestibular/ear
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• at 5-12 weeks, homozygotes show degeneration of OHC stereociliary bundles mainly in the apical cochlear turn
• at 6 weeks, no tufts of OHC hair bundles are observed in the apical turn, although OHC cell bodies appear intact
• in contrast, homozygotes display normal stereociliary bundle morphology of OHCs in the basal turn and of IHCs in all cochlear turns
• consistent with a normal balance, stereociliary bundles of the utricle and saccule appear morphologically intact
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• at 5-12 weeks, homozygotes exhibit OHC loss at the apical cochlea
• however, no apparent abnormalities are detected in the basal cochlea and the vestibule
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• in contrast to IHCs, P1 mutant apical OHCs do not express Ba2+ permeable inward current channels
• in contrast to OHCs at the apical cochlea, mutant OHCs at the basal turn show substantial residual Ba2+ currents following application of nimodipine
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• homozygotes display significantly elevated auditory brainstem response (ABR) thresholds for a broadband click relative to wild-type littermates
(J:72316)
• at 5-8 weeks, all homozygotes exhibit no auditory brainstem responses at 100 dB SPL
(J:118306)
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• homozygotes produce little or no DPOAEs at low frequencies relative to wild-type or heterozygous littermates
• however, at 20-48 kHz, homozygotes yield low but moderate-level DPOAEs that are similar to those of wild-type mice
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• at 5-8 weeks, all homozygotes are deaf
(J:118306)
• surprisingly, hearing loss is not associated with major changes in IHC structure
(J:118306)
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nervous system
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• at 5-12 weeks, homozygotes show degeneration of OHC stereociliary bundles mainly in the apical cochlear turn
• at 6 weeks, no tufts of OHC hair bundles are observed in the apical turn, although OHC cell bodies appear intact
• in contrast, homozygotes display normal stereociliary bundle morphology of OHCs in the basal turn and of IHCs in all cochlear turns
• consistent with a normal balance, stereociliary bundles of the utricle and saccule appear morphologically intact
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• at 5-12 weeks, homozygotes exhibit OHC loss at the apical cochlea
• however, no apparent abnormalities are detected in the basal cochlea and the vestibule
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• in contrast to IHCs, P1 mutant apical OHCs do not express Ba2+ permeable inward current channels
• in contrast to OHCs at the apical cochlea, mutant OHCs at the basal turn show substantial residual Ba2+ currents following application of nimodipine
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• homozygotes show a significant reduction in the number of neurons and myelinated fibers in some regions of the spiral ganglion
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cellular
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• homozygotes exhibit impairment of postnatal pancreatic beta cell generation
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• BrdU-labeling indicates a significant reduction in the proliferation rate of mutant beta cells at P14 and P30
• however, no increase in cell death of mutant islets is observed at these stages
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