Preserved otolith organ function in caspase-3-deficient mice with impaired horizontal semicircular canal function

Abstract

Genetically engineered mice are valuable models for elucidation of auditory and vestibular pathology. Our goal was to establish a comprehensive vestibular function testing system in mice using: 1) horizontal angular vestibular-ocular reflex (hVOR) to evaluate semicircular canal function, and 2) otolith-ocular reflex (OOR) to evaluate otolith organ function, and to validate the system by characterizing mice with vestibular dysfunction. We used pseudo-off vertical axis rotation (pOVAR) to induce an otolith-only stimulus using a custom-made centrifuge. For the OOR, horizontal slow phase eye velocity (HEV) and vertical eye position (VEP) was evaluated as a function of acceleration. Using this system, we characterized hVOR and OOR in the caspase-3 (Casp3) mutant mice. Casp3 −/− mice had severely impaired hVOR gain, while Casp3 +/− mice had an intermediate response compared to WT mice. Evaluation of OOR revealed that at low to mid frequencies and stimulus intensity, Casp3 mutants and WT mice had similar responses. At higher frequencies and stimulus intensity, the Casp3 mutants displayed mildly reduced otolith organ related responses. These findings suggest that the Casp3 gene is important for the proper function of the semicircular canals but less important for the otolith organ function.

Apoptotic cell death in disease—Current understanding of the NCCD 2023

“…A similar impact of genetic background on phenotype has also been observed for Apaf1 −/− and Casp9 −/− mice [1282,1283]. Although Casp3 −/− mice reach adulthood on a C57BL/6 background, they exhibit defects in complex brain functions including attention and (in males) social behavior [1284,1285], as well as ear and vestibular dysfunction including hearing loss [1286][1287][1288][1289][1290], Abnormalities were also seen in the kidney and spleen of aged Casp3 −/− mice [1291]. Survival of Casp3 −/− mice to adulthood in C57BL/6 mice was ascribed to the compensatory activation of CASP7 [1292].…”

Berberine inhibits the chemotherapy‐induced repopulation by suppressing the arachidonic acid metabolic pathway and phosphorylation of FAK in ovarian cancer

“…The combination of chemotherapy and pan caspase inhibitor may be beneficial in cancer treatment, especially the promising result from pan caspase inhibitor in clinical trial for hepatitis C, non‐alcoholic steatohepatitis and liver reperfusion injury . However, the activity of caspase 3 often is required for chemotherapy‐, radiotherapy‐ and many targeted therapy‐induced apoptosis and may directly associate the patient's response or survival, to say nothing of the issue with female fertility or development of eye and ear due to lack of caspase 3 . Therefore, targeting another key molecular of “Phoenix Rising” pathway would be more reasonable and safer.…”

“…31,32 However, the activity of caspase 3 often is required for chemotherapy-, radiotherapy-and many targeted therapy-induced apoptosis and may directly associate the patient's response or survival, to say nothing of the issue with female fertility or development of eye and ear due to lack of caspase 3. 33 Therefore, targeting another key molecular of "Phoenix Rising" pathway would be more reasonable and safer. Being a potent promoter of cell proliferation, motility, invasion and angiogenesis, 22 the effect of PGE 2 promoting the growth of tumour cells has been reported in variety of cancers, such as colon cancer, lung cancer and ovarian cancer.…”

Dopamine Modulates Motor Control in a Specific Plane Related to Support

“…We retrieved the same result in Isk-/- mice, years later in a study focused on vestibular neurons in this mutant [ 27 ]. A recent paper by Armstrong and collaborators (2015) [ 28 ] showed that caspase deficient mice with impaired horizontal semicircular canal function and intact otolithic function circle but do not exhibit barrel rolling. Altogether, our results and those of previous studies show that a congenital lack of vestibular function results in a major asymmetry in striatal function, which in turn is causally related to circling.…”