mortality/aging
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• Background Sensitivity: on a predominantly CD-1 background, 45% of the expected double homozygotes survive as adults whereas only 6% of the expected double homozygotes survive as adults on a 129 background
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behavior/neurological
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• Background Sensitivity: on a predominantly CD-1 background (5 to 9 backcross generations), 100% of double homozygotes that survive to adulthood exhibit circling; in contrast, none of the small number of 129 double homozygotes that survive to adulthood circle
• cicling is first evident when pups are old enough to walk and continues into adulthood
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nervous system
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• at E13.5, double homozygotes show delayed outgrowth of efferent projections into both the ipsilateral and contralateral inner ears
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• at E13.5, both ipsilateral and contralateral projections of inner ear efferent (IEE) axons are disoriented and exhibit a temporary difficulty in reaching their targets
• as a result, ectopic caudal extensions are formed at the midline of the hindbrain with a 1- to 2-day delay in arriving at the ear end organs
• at E14.5 or later, axon tracing of IEEs shows a fairly normal number of crossed and uncrossed fibers in mutant mice
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• at E13.5, double homozygotes display delayed growth of efferent projections into both the ipsilateral and contralateral inner ears
• at this stage, growth cones have not yet reached into the sensory epithelia of the semicircular canals and there is an aberrant pausity of axons destined for the saccule and utricle
• in contrast, growth of afferent projections into the inner ear are normal, with afferents reaching all sensory epithelia by E12.5
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hearing/vestibular/ear
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• all adult circling mutants display much thinner semicircular canals (SCCs), with a significantly reduced (5-fold) cross-sectional diameter, esp. in the anterior vertical SCC
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• at P21, circling double homozygotes display loosely associated basolateral membranes in vestibular dark cells as well as severe extracellular edema
• in addition, the apical surface of dark cells facing the endolymph-filled lumen shows an accumulation of fluid-filled vesicles
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• at P7, the endolymph-filled membranous ducts are severely reduced by 53-fold in accord with a collapsed lumen and deflated SCCs
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• on a CD-1 background, reduced endolymph-filled lumens lead to a significant reduction in the flow of endolymph fluid through the semicircular canals
• [K+] is significantly reduced from a mean of 118 mM in wild-type mice to 29 mM in double homozygotes
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• on a CD-1 background, transepithelial utricular potential (UP) of the vestibular endolymph is significantly reduced from a mean of 0.4 mV in wild-type mice to -14.0 mV in double homozygotes
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• on a CD-1 background, double homozygotes fail to properly regulate the ionic homeostasis of vestibular endolymph
• however, blood hematocrit, [K+], and osmolarity appear to be nomal
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• severe vestibular dysfunction is associated with a drastic reduction in the volume of endolymph fluid within the vestibular apparatus
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digestive/alimentary system
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• severe cleft palate in 15% of mice at E18.5
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• about a 50% decrease in the number of proliferating cells is seen in the colon; however, no change in the number of apoptotic cells is seen
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• in the small intestine Paneth cells are displaced from the base of the crypts by proliferating cells while the number of proliferating cells in the normal progenitor niche (along the sides of the crypt) are reduced
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endocrine/exocrine glands
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• about a 50% decrease in the number of proliferating cells is seen in the colon; however, no change in the number of apoptotic cells is seen
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• in the small intestine Paneth cells are displaced from the base of the crypts by proliferating cells while the number of proliferating cells in the normal progenitor niche (along the sides of the crypt) are reduced
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craniofacial
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• severe cleft palate in 15% of mice at E18.5
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cellular
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• at E13.5, double homozygotes show delayed outgrowth of efferent projections into both the ipsilateral and contralateral inner ears
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• at E13.5, both ipsilateral and contralateral projections of inner ear efferent (IEE) axons are disoriented and exhibit a temporary difficulty in reaching their targets
• as a result, ectopic caudal extensions are formed at the midline of the hindbrain with a 1- to 2-day delay in arriving at the ear end organs
• at E14.5 or later, axon tracing of IEEs shows a fairly normal number of crossed and uncrossed fibers in mutant mice
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growth/size/body
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• severe cleft palate in 15% of mice at E18.5
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