Inner ear dysfunction in caspase-3 deficient mice

Makishima, Tomoko; Hochman, Lara; Armstrong, P.; Rosenberger, E.; Ridley, Ryan W.; Woo, Minna; Perachio, Adrian A.; Wood, Scott J.

doi:10.1186/1471-2202-12-102

Cited by 26 publications

(25 citation statements)

References 42 publications

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“…The experimental setup, apparatus, procedures for recording and data analysis were identical to those described in the previous studies in our laboratory [17, 34, 35]. Briefly, ten minutes before the start of recordings, animals were treated with pilocarpine (4%) eye drops to limit pupil dilation in darkness.…”

Section: Methodsmentioning

confidence: 99%

“…Data were stored on a computer along with stimulation parameters, including velocity and position profiles of motion control axes and analyzed with a custom interactive script (MATLAB, The MathWork Inc., Natic, MA, USA). Eye position signals were calibrated off-line using obtained calibration scale factors based on the ocular image verified by rotating a camera from the perspective of the optic axis [34]. Pupil position was differentiated and desaccaded using velocity thresholds to obtain slow phase eye velocity.…”

Section: Methodsmentioning

confidence: 99%

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The role of GABAB receptors in the vestibular oculomotor system in mice

Shimizu

Wood

Kushiro

et al. 2016

Behavioural Brain Research

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Systemic administration of a gamma-amino butyric acid type B (GABAB) receptor agonist, baclofen, affects various physiological and psychological processes. To date, the effects on oculomotor system have been well characterized in primates, however those in mice have not been explored. In this study, we investigated the effects of baclofen focusing on vestibular-related eye movements. Two rotational paradigms, i.e. sinusoidal rotation and counter rotation were employed to stimulate semicircular canals and otolith organs in the inner ear. Experimental conditions (dosage, routes and onset of recording) were determined based on the prior studies exploring the behavioral effects of baclofen in mice. With an increase in dosage, both canal and otolith induced ocular responses were gradually affected. There was a clear distinction in the drug sensitivity showing that eye movements derived from direct vestibulo-ocular reflex pathways were relatively unaltered, while the responses through higher-order neural networks in the vestibular system were substantially decreased. These findings were consistent with those observed in primates suggesting a well-conserved role of GABAB receptors in the oculomotor system across frontal-eyed and lateral-eyed animals. We showed here a previously unrecognized effect of baclofen on the vestibular oculomotor function in mice. When interpreting general animal performance under the drug, the potential contribution of altered balance system should be taken into consideration.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The role of GABAB receptors in the vestibular oculomotor system in mice

Shimizu

Wood

Kushiro

et al. 2016

Behavioural Brain Research

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“…Most of the techniques for eye movement recording were similar to those described in a previous study in our laboratory (Makishima et al, 2011). Before each trial session, mice were briefly anesthetized with Isoflurane and treated with Pilocarpine (2%) eye drops to limit pupil dilation in darkness.…”

Section: Methodsmentioning

confidence: 99%

Dynamic characteristics of otolith ocular response during counter rotation about dual yaw axes in mice

et al. 2015

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The central vestibular system plays an important role in higher neural functions such as self-motion perception and spatial orientation. Its ability to store head angular velocity is called velocity storage mechanism (VSM), which has been thoroughly investigated across a wide range of species. However, little is known about the mouse VSM, because the mouse lacks typical ocular responses such as optokinetic after nystagmus or a dominant time constant of vestibulo-ocular reflex for which the VSM is critical. Experiments were conducted to examine the otolith-driven eye movements related to the VSM and verify its characteristics in mice. We used a novel approach to generate a similar rotating vector as a traditional off-vertical axis rotation (OVAR) but with a larger resultant gravito-inertial force (>1 g) by using counter rotation centrifugation. Similar to results previously described in other animals during OVAR, two components of eye movements were induced, i.e. a sinusoidal modulatory eye movement (modulation component) on which a unidirectional nystagmaus (bias component) was superimposed. Each response is considered to derive from different mechanisms; modulations arise predominantly through linear vestibulo-ocular reflex, whereas for the bias, the VSM is responsible. Data indicate that the mouse also has a well-developed vestibular system through otoliths inputs, showing its highly conserved nature across mammalian species. On the other hand, to reach a plateau state of bias, a higher frequency rotation or a larger gravito-inertial force was considered to be necessary than other larger animals. Compared with modulation, the bias had a more variable profile, suggesting an inherent complexity of higher-order neural processes in the brain. Our data provides the basis for further study of the central vestibular system in mice, however, the underlying individual variability should be taken into consideration.

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“…For example, caspase-3 activity is important for remodeling the cytoplasm and in the development of eye lens and inner ear (9,10). Caspase-3 is also involved in differentiation of many cell types, such as erythroblasts, keratinocytes, macrophages, lens epithelial cells, sperm cells, skeletal muscles, embryonic stem cells (ESCs), osteoblasts, and placental trophoblasts (8,(11)(12)(13).…”

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confidence: 99%

Modifications to a common phosphorylation network provide individualized control in caspases

Thomas

Grinshpon

Swartz

et al. 2018

Journal of Biological Chemistry

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Caspase-3 activation and function has been well defined during programmed cell death, but caspase activity, at low levels, is also required for developmental processes such as lymphoid proliferation and erythroid differentiation.Post-translational modification of caspase-3 is one method used by cells to fine-tune activity below the threshold required for apoptosis, but the allosteric mechanism that reduces activity is unknown. Phosphorylation of caspase-3 at a conserved allosteric site by p38-MAPK promotes survival in human neutrophils, and the modification of the loop is thought to be a key regulator in many developmental processes. We utilized phylogenetic, structural, and biophysical studies to define the interaction networks that facilitate the allosteric mechanism in caspase-3. We show that, within the modified loop, S150 evolved with the apoptotic caspases, while T152 is a more recent evolutionary event in mammalian caspase-3. Substitutions at S150 result in a pH-dependent decrease in dimer stability, and localized changes in the modified loop propagate to the active site of the same protomer through a connecting surface helix. Likewise, a cluster of hydrophobic amino acids connects the conserved loop to the active site of the second protomer. The presence of T152 in the conserved loop introduces a "kill switch" in mammalian caspase-3 while the more ancient S150 reduces without abolishing enzyme activity. These data reveal how evolutionary changes in a conserved allosteric site result in both a common pathway for lowering activity during development as well as introducing a more recent cluster-specific switch to abolish activity.

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Inner ear dysfunction in caspase-3 deficient mice

Cited by 26 publications

References 42 publications

The role of GABAB receptors in the vestibular oculomotor system in mice

The role of GABAB receptors in the vestibular oculomotor system in mice

Dynamic characteristics of otolith ocular response during counter rotation about dual yaw axes in mice

Modifications to a common phosphorylation network provide individualized control in caspases

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