All Phenotypes Tmtc4<tm1(KOMP)Vlcg> MGI Mouse

cochlear hair cell degeneration ( J:268046 )

• immunohistochemistry of cochlear explants revealed progressive loss of first outer hair cell (OHCs) and then inner hair cells (IHCs) at the cochlear base and subsequently at the mid-turn and apex

cochlear inner hair cell degeneration ( J:268046 )

cochlear outer hair cell degeneration ( J:268046 )

degeneration of organ of Corti supporting cells ( J:268046 )

• by P26, mice show degeneration of the supporting cell network in the organ of Corti

cochlear degeneration ( J:268046 )

• mice show generalized and progressive cochlear degeneration affecting first hair cells, and subsequently the supporting cell network and spiral ganglion neurons

organ of Corti degeneration ( J:268046 )

• at P30, degeneration of the organ of Corti is observed in all cochlear turns

abnormal auditory brainstem response waveform shape ( J:268046 )

• at P26, ABR waveforms indicate absent ABR responses to click stimuli at multiple sound pressure levels (SPL)

increased or absent threshold for auditory brainstem response ( J:268046 )

• at P26, mice show significantly increased ABR thresholds in response to both broadband click and a range of pure-tone frequencies relative to wild-type or heterozygous control mice

• however, ABR thresholds to broadband click stimuli are normal at P13

absent distortion product otoacoustic emissions ( J:268046 )

• DPOAEs are absent at P26

sensorineural hearing loss ( J:268046 )

• mice exhibit early onset, rapidly progressive hearing loss and become nearly completely deaf by P23

cochlear hair cell degeneration ( J:268046 )

• immunohistochemistry of cochlear explants revealed progressive loss of first outer hair cell (OHCs) and then inner hair cells (IHCs) at the cochlear base and subsequently at the mid-turn and apex

cochlear inner hair cell degeneration ( J:268046 )

cochlear outer hair cell degeneration ( J:268046 )

cochlear ganglion degeneration ( J:268046 )

• at 4 months of age, mice show degeneration of the spiral ganglion neurons

• however, the spiral ganglion is preserved at P30

increased sensitivity to induced cell death ( J:268046 )

• thapsigargin-treated neonatal skin fibroblasts show significantly higher protein levels of Chop as well as the downstream UPR protein DR5, and the apoptosis marker cleaved caspase 8 relative to similarly-treated wild-type fibroblasts

• thapsigargin-treated neonatal cochlear explant cultures show elevated caspase 3 mRNA levels (indicating apoptosis) relative to similarly-treated wild-type cultures

abnormal endoplasmic reticulum physiology ( J:268046 )

• cochleae exhibit significantly increased spontaneous Ca²⁺ wave frequency, higher [Ca²⁺]i peak levels, and significantly longer decay time of [Ca²⁺] return to baseline, suggesting impaired Ca²⁺ reuptake into the endoplasmic reticulum

increased endoplasmic reticulum stress ( J:268046 )

• thapsigargin-treated neonatal skin fibroblasts exhibit upregulation of the unfolded protein response (UPR), as shown by significantly higher mRNA levels of 3 genes (Chop, S-XBP1, and BiP) relative to similarly-treated wild-type fibroblasts

• steady-state Chop protein levels are markedly higher than those in wild-type fibroblasts, with 29.9% of cells versus 0.5% of wild-type cells showing expression levels above threshold, even in the absence of thapsigargin

• thapsigargin-treated neonatal cochlear explant cultures show significantly higher mRNA levels of UPR activators (Chop, S-XBP1, and BiP) as well as elevated caspase 3 mRNA levels (indicating apoptosis) relative to similarly-treated wild-type cultures

abnormal calcium ion homeostasis ( J:268046 )

• cochleae exhibit significantly increased spontaneous Ca²⁺ wave frequency, higher [Ca²⁺]i peak levels, and significantly longer decay time of [Ca²⁺] return to baseline, suggesting impaired Ca²⁺ reuptake into the endoplasmic reticulum

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

Contributing Projects: Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO)
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