Control of stereocilia length during development of hair bundles

Krey, Jocelyn F.; Chatterjee, Paroma; Halford, Julia; Cunningham, Christopher L.; Perrin, Benjamin J.; Barr-Gillespie, Peter G.

doi:10.1101/2022.12.18.520962

Cited by 7 publications

(14 citation statements)

References 102 publications

(245 reference statements)

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“…By contrast, EPS8 shifted from having most labeling at row 1 tips in Ush1g bw /+ bundles (arrow in Figure 7C) to nearly identical levels at both row 1 and 2 tips in Ush1g bw/bw bundles (double arrow in Figure 7D). This broadened distribution of EPS8 resembled that seen in Pcdh15 av3J/av3J and Cdh23 v2J/v2J mutants 31 . MYO15A showed a similar altered distribution; while most MYO15A was found at row 1 tips in Ush1g bw /+ bundles (Figure 7E), its overall level was reduced in Ush1g bw/bw bundles and it was evenly distributed between rows 1 and 2 (Figure 7F).…”

Section: Resultssupporting

confidence: 55%

“…Homozygous null mutations in Cdh23 and Pcdh15 lead to altered distribution of proteins that concentrate at the tips of row 1 stereocilia in postnatal hair bundle development 31 . While localization of GPSM2 and GNAI3 was only modestly affected, EPS8 shifted from being primarily found at row 1 tips to being equally distributed between row 1 and 2 tips.…”

Section: Discussionmentioning

confidence: 99%

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Spontaneous allelic variant in deafness–blindness gene Ush1g resulting in an expanded phenotype

Vartanian

Krey

Chatterjee

et al. 2023

Genes Brain and Behavior

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Relationships between novel phenotypic behaviors and specific genetic alterations are often discovered using target‐specific, directed mutagenesis or phenotypic selection following chemical mutagenesis. An alternative approach is to exploit deficiencies in DNA repair pathways that maintain genetic integrity in response to spontaneously induced damage. Mice deficient in the DNA glycosylase NEIL1 show elevated spontaneous mutations, which arise from translesion DNA synthesis past oxidatively induced base damage. Several litters of Neil1 knockout mice included animals that were distinguished by their backwards‐walking behavior in open‐field environments, while maintaining frantic forward movements in their home cage environment. Other phenotypic manifestations included swim test failures, head tilting and circling. Mapping of the mutation that conferred these behaviors showed the introduction of a stop codon at amino acid 4 of the Ush1g gene. Ush1gbw/bw null mice displayed auditory and vestibular defects that are commonly seen with mutations affecting inner‐ear hair‐cell function, including a complete lack of auditory brainstem responses and vestibular‐evoked potentials. As in other Usher syndrome type I mutant mouse lines, hair cell phenotypes included disorganized and split hair bundles, as well as altered distribution of proteins for stereocilia that localize to the tips of row 1 or row 2. Disruption to the bundle and kinocilium displacement suggested that USH1G is essential for forming the hair cell's kinocilial links. Consistent with other Usher type 1 models, Ush1gbw/bw mice had no substantial retinal degeneration compared with Ush1gbw/+ controls. In contrast to previously described Ush1g alleles, this new allele provides the first knockout model for this gene.

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Section: Resultssupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Spontaneous allelic variant in deafness–blindness gene Ush1g resulting in an expanded phenotype

Vartanian

Krey

Chatterjee

et al. 2023

Genes Brain and Behavior

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View full text Add to dashboard Cite

show abstract

“…6D). This broadened distribution of EPS8 resembled that seen in Pcdh15 av3J/av3J and Cdh23 v2J/v2J mutants 28 . MYO15A showed a similar altered distribution; while most MYO15A was found at row 1 tips in Ush1g bw /+ bundles (Fig.…”

Section: Resultssupporting

confidence: 52%

“…While localization of GPSM2 and GNAI3 was only modestly affected, EPS8 shifted from being primarily found at row 1 tips to being equally distributed between row 1 and 2 tips. We also showed that CDH23 and PCDH15 play an underappreciated role in coordinating the lengths of adjacent stereocilia 28 . Row 1 proteins showed similar altered distribution in Ush1g bw/bw , and adjacent stereocilia lengths were less coordinated, albeit not as profoundly disrupted as in Cdh23 v2J/v2J and Pcdh15 av3J/av3J hair cells.…”

Section: Discussionmentioning

confidence: 69%

“…Homozygous null mutations in Cdh23 and Pcdh15 lead to altered distribution of proteins that concentrate at the tips of row 1 stereocilia in postnatal hair bundle development 28 . While localization of GPSM2 and GNAI3 was only modestly affected, EPS8 shifted from being primarily found at row 1 tips to being equally distributed between row 1 and 2 tips.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Spontaneous allelic variant inUsh1gresulting in an expanded phenotype

Vartanian

Krey

Chatterjee

et al. 2023

Preprint

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Strategies to reveal the discovery of the relationships between novel phenotypic behaviors and specific genetic alterations can be achieved via either target-specific, directed mutagenesis or phenotypic selection following random chemical mutagenesis. As an alternative approach, one can exploit deficiencies in DNA repair pathways that are responsible for the maintenance of genetic integrity in response to spontaneously-induced damage. In the genetic background of mice deficient in the DNA glycosylase NEIL1, elevated numbers of spontaneous mutations arise from translesion DNA synthesis past unrepaired, oxidatively-induced base damage. Several litters ofNeil1knockout mice included animals that were distinguished by their backwards-walking behavior in open-field environments, while maintaining frantic forward movements in their home cage environment. Other phenotypic manifestations included swim test failures, head tilting, and circling. Mapping of the mutation that conferred these behaviors revealed the introduction of a stop codon at amino acid 4 of theUsh1ggene; the allele wasUsh1gbw, reflecting the backwards-walking phenotype.Ush1gbw/bwnull mice displayed auditory and vestibular defects that are commonly seen with mutations affecting inner-ear hair-cell function, including a complete lack of auditory brainstem responses and vestibular-evoked potentials. As in other Usher syndrome type I mutant mouse lines, hair-cell phenotypes included disorganized and split hair bundles, as well as altered distribution of proteins for stereocilia that localize to the tips of row 1 or row 2. Disruption to the bundle and kinocilium displacement suggested that USH1G is essential for forming the hair cell’s kinocilial links. Due to the vestibular dysfunction, however, visual behavior as measured with optokinetic tracking could not be assessed inUsh1gbw/bwmice. Consistent with other Usher type 1 models, however,Ush1gbw/bwmice had no substantial retinal degeneration compared toUsh1gbw/+controls out to six months. In contrast to previously-describedUsh1galleles, this new allele provides the first knockout model for this gene.

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Inhibitory G proteins play multiple roles to polarize sensory hair cell morphogenesis

Jarysta,

Tadenev,

Day

et al. 2023

Preprint

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Inhibitory G alpha (GNAI or Gαi) proteins are critical for the polarized morphogenesis of sensory hair cells and for hearing. The extent and nature of their actual contributions remains unclear, however, as previous studies did not investigate all GNAI proteins and included non-physiological approaches. Pertussis toxin can downregulate functionally redundant GNAI1, GNAI2, GNAI3 and GNAO proteins, but may also induce unrelated defects. Here we directly and systematically determined the role(s) of each individual GNAI protein in mouse auditory hair cells. GNAI2 and GNAI3 are similarly polarized at the hair cell apex with their binding partner GPSM2, whereas GNAI1 and GNAO are neither detected nor polarized. In Gnai3 mutants, GNAI2 progressively fails to fully occupy the subcellular compartments where GNAI3 is missing. In contrast, GNAI3 can fully compensate for the loss of GNAI2 and is essential for hair bundle morphogenesis and auditory function. Simultaneous inactivation of Gnai2 and Gnai3 recapitulates for the first time two distinct types of defects only observed so far with pertussis toxin: 1) a delay or failure of the basal body to migrate off-center in prospective hair cells, and 2) a reversal in the orientation of some hair cell types. We conclude that GNAI proteins are critical for hair cells to break planar symmetry and to orient properly before GNAI2/3 regulate hair bundle morphogenesis with GPSM2.

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Control of stereocilia length during development of hair bundles

Cited by 7 publications

References 102 publications

Spontaneous allelic variant in deafness–blindness gene Ush1g resulting in an expanded phenotype

Spontaneous allelic variant in deafness–blindness gene Ush1g resulting in an expanded phenotype

Spontaneous allelic variant inUsh1gresulting in an expanded phenotype

Inhibitory G proteins play multiple roles to polarize sensory hair cell morphogenesis

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