Mutational ataxia resulting from abnormal vestibular acquisition and processing is partially compensated for.

Kopecky, Benjamin; DeCook, Rhonda; Fritzsch, Bernd

doi:10.1037/a0026896

Cited by 19 publications

(37 citation statements)

References 63 publications

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“…While there was substantial lengthening of the organ of Corti from P0 to P21 for both WTs (3.36+/−0.094mm vs. 4.71+/−0.27mm; p<0.001) and dCKOs (3.40+/−0.13mm vs. 4.79+/−0.27mm; p<0.001), there was no significant change between P21 and four months of age for WTs (4.71+/−0.27mm vs. 4.78+/−0.062mm; p=0.558) and dCKOs (4.79+/−0.27mm vs. 4.76+/−0.17mm; p=0.779) (Figure 2G). These WT length measurements were consistent with previously published data (Kopecky et al, 2011; Kopecky et al, 2012a; Pan et al, 2011). Furthermore, equivalence testing confirmed that P0 WT and P0 dCKO mice (df=26) were identical and P21 WT and P21 dCKO mice (df=26) as well as four month WT and four month dCKO mice (df=26) were the same (Figure 3A).…”

Section: Resultssupporting

confidence: 93%

“…Furthermore, equivalence testing confirmed that P0 WT and P0 dCKO mice (df=26) were identical and P21 WT and P21 dCKO mice (df=26) as well as four month WT and four month dCKO mice (df=26) were the same (Figure 3A). Our data suggest that the loss of both N-Myc and L-Myc in differentiated hair cells had no effect on the length of the organ of Corti (Figure 2) or its overall development (Figure 1); this contrasted with the disorganization and loss of hair cells as well as the reduction in length of the organ of Corti in the Pax2-Cre N-Myc CKO mice at P21 as previously reported (Dominguez-Frutos et al, 2011; Kopecky et al, 2011; Kopecky et al, 2012a). Figs 2 and 3…”

Section: Resultssupporting

confidence: 76%

“…Manipulation of these, or a subset of these, genes coupled with other yet-to-be defined genes may play a future therapeutic role in protecting hair cells. To this end, our recent data on Pax2-Cre N-Myc single conditional knockout (CKO) mice suggests a previously unexplored importance of the proto-oncogene N-Myc on long-term hair cell maintenance (Dominguez-Frutos et al, 2011; Kopecky et al, 2011; Kopecky et al, 2012a). Pax2-Cre N-Myc CKO mice have an initial formation of both cochlear and vestibular hair cells with subsequent loss of cochlear hair cells (Kopecky, et al, 2011) beginning around postnatal day 21 (P21) and complete loss of cochlear hair cells by nine months of age (Kopecky et al, 2012a).…”

Section: Introductionmentioning

confidence: 99%

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N-Myc and L-Myc are essential for hair cell formation but not maintenance

2012

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Sensorineural hearing loss results from damage to the hair cells of the organ of Corti and is irreversible in mammals. While hair cell regeneration may prove to be the ideal therapy after hearing loss, prevention of initial hair cell loss could provide even more benefit at a lower cost. Previous studies have shown that the deletion of Atoh1 results in embryonic loss of hair cells while the absence of Barhl1, Gfi1, and Pou4f3 leads to the progressive loss of hair cells in newborn mice. We recently reported that in the early embryonic absence of N-Myc (using Pax2-Cre), hair cells in the organ of Corti develop and remain until at least seven days after birth, with subsequent progressive loss. Thus, N-Myc plays a role in hair cell viability; however, it is unclear if this is due to its early expression in hair cell precursors and throughout the growing otocyst as it functions through proliferation or its late expression exclusively in differentiated hair cells. Furthermore, the related family member L-Myc is mostly co-expressed in the ear, including in differentiated hair cells, but its function has not been studied and could be partially redundant to N-Myc. To test for a long-term function of the Mycs in differentiated hair cells, we generated nine unique genotypes knocking out N-Myc and/or L-Myc after initial formation of hair cells using the well-characterized Atoh1-Cre. We tested functionality of the auditory and vestibular systems at both P21 and four months of age and under the administration of the ototoxic drug cisplatin. We conclude that neither N-Myc nor L-Myc is likely to play important roles in long-term hair cell maintenance. Therefore, it is likely that the late-onset loss of hair cells resulting from early deletion of the Mycs leads to an unsustainable developmental defect.

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Section: Resultssupporting

confidence: 93%

Section: Resultssupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

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N-Myc and L-Myc are essential for hair cell formation but not maintenance

2012

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“…Catwalk assay was performed for gait analysis using Noldus system (Wageningen, Netherlands) as previously reported (Kopecky, Decook et al 2012). Mice were placed at the end of a corridor and allowed to move freely.…”

Section: Methodsmentioning

confidence: 99%

Genetic reduction of mitochondrial complex I function does not lead to loss of dopamine neurons in vivo

Kim

Choi

Sorscher

et al. 2015

Neurobiology of Aging

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Inhibition of mitochondrial complex I activity is hypothesized to be one of the major mechanisms responsible for dopaminergic neuron death in Parkinson’s disease. However, loss of complex I activity by systemic deletion of the Ndufs4 gene, one of the subunits comprising complex I, does not cause dopaminergic neuron death in culture. Here we generated mice with conditional Ndufs4 knockout in dopaminergic neurons (Ndufs4 cKO) to examine the effect of complex I inhibition on dopaminergic neuron function and survival during aging and upon MPTP treatment in vivo. Ndufs4 cKO mice did not show enhanced dopaminergic neuron loss in the SNpc or dopamine-dependent motor deficits over the 24-month lifespan. These mice were just as susceptible to MPTP as control mice. However, compared to control mice, Ndufs4 cKO mice exhibited an age-dependent reduction of dopamine in the striatum and increased α-synuclein phosphorylation in dopaminergic neurons of the SNpc. We also utilized an inducible Ndufs4 knockout mouse strain (Ndufs4 iKO) in which Ndufs4 is conditionally deleted in all cells in adult to examine the effect of adult onset, complex I inhibition on MPTP sensitivity of dopaminergic neurons. The Ndufs4 iKO mice exhibited similar sensitivity to MPTP as control littermates. These data suggest that mitochondrial complex I inhibition in dopaminergic neurons does contribute to dopamine loss and the development of α-synuclein pathology. However, it is not sufficient to cause cell- autonomous dopaminergic neuron death during the normal lifespan of mice. Furthermore, mitochondrial complex I inhibition does not underlie MPTP toxicity in vivo in either cell autonomous or non-autonomous manner. These results provide strong evidence that inhibition of mitochondrial complex I activity is not sufficient to cause dopaminergic neuron death during aging nor does it contribute to dopamine neuron toxicity in the MPTP model of Parkinson’s disease. These findings suggest the existence of alternative mechanisms of dopaminergic neuron death independent of mitochondrial complex I inhibition.

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“…The automated CatWalk gait analysis method is also applied in models involving other types of pain and peripheral nerve damage and movement disorders like Parkinson's disease [21][22][23]. Abnormal gait was described in mice exhibiting (cerebellar) ataxia, by using paw print area, contact area, base of support of the hindpaws, stand, swing and step regularity [24][25][26]. The aim of this study was to identify gait changes in the Ndufs4 −/− mouse by using the CatWalk system.…”

Section: Introductionmentioning

confidence: 99%