Grxcr1 Promotes Hair Bundle Development by Destabilizing the Physical Interaction between Harmonin and Sans Usher Syndrome Proteins

Blanco-Sánchez, Bernardo; Clément, Aurélie; Fierro, Javier; Stednitz, Sarah J.; Phillips, Jennifer B.; Wegner, Jeremy; Panlilio, Jennifer M.; Peirce, Judy; Washbourne, Philip; Westerfield, Monte

doi:10.1016/j.celrep.2018.10.005

Cited by 11 publications

(14 citation statements)

References 47 publications

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“…We next asked whether the increase in the number of ER–mitochondria associations in pappaa p170 hair cells was due to an overabundance of ER. We used an antibody shown to specifically label KDEL ( Blanco-Sánchez et al, 2018 ; Blanco-Sánchez et al, 2014 ), an ER C-terminal peptide retention signal ( Munro and Pelham, 1987 ), to visualize the ER in the transgenic line Tg(brn3c:mGFP) , in which the lateral line hair cells are labeled with membrane-targeted GFP ( Figure 1F ). We measured the percentage of area occupied by KDEL immunofluorescence per neuromast using an approach previously described ( Blanco-Sánchez et al, 2014 ).…”

Section: Resultsmentioning

confidence: 99%

Pregnancy-associated plasma protein-aa regulates endoplasmic reticulum–mitochondria associations

Alassaf

Halloran

2021

eLife

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Endoplasmic reticulum (ER) and mitochondria form close physical associations to facilitate calcium transfer, thereby regulating mitochondrial function. Neurons with high metabolic demands, such as sensory hair cells, are especially dependent on precisely regulated ER-mitochondria associations. We previously showed that the secreted metalloprotease Pregnancy associated plasma protein-aa (Pappaa) regulates mitochondrial function in zebrafish lateral line hair cells (Alassaf et al., 2019). Here, we show that pappaa mutant hair cells exhibit excessive and abnormally close ER-mitochondria associations, suggesting increased ER-mitochondria calcium transfer. pappaa mutant hair cells are more vulnerable to pharmacological induction of ER-calcium transfer. Additionally, pappaa mutant hair cells display ER stress and dysfunctional downstream processes of the ER-mitochondria axis including altered mitochondrial morphology and reduced autophagy. We further show that Pappaa influences ER-calcium transfer and autophagy via its ability to stimulate insulin-like growth factor-1 bioavailability. Together our results identify Pappaa as a novel regulator of the ER-mitochondria axis.

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Section: Resultsmentioning

confidence: 99%

Pregnancy-associated plasma protein-aa regulates endoplasmic reticulum–mitochondria associations

Alassaf

Halloran

2021

eLife

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“…The mechanoelectrical transduction process in the cochlea is essential for the conversion of mechanical signals into chemical responses, to communicate sound signals to the brain (Grati and Kachar, 2011;Blanco-Sanchez et al, 2018). MET relies on the appropriate organization of actin-based stereocilia to open the potassium channels and depolarize the cells (Corns et al, 2018).…”

Section: Mechanoelectrical Transductionmentioning

confidence: 99%

“…MET relies on the appropriate organization of actin-based stereocilia to open the potassium channels and depolarize the cells (Corns et al, 2018). Mutations causing abnormal development of these HC structures can disrupt the MET process, contributing to SNHL and deafness (Blanco-Sanchez et al, 2018).…”

Section: Mechanoelectrical Transductionmentioning

confidence: 99%

Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy

Whatley

Francis

et al. 2020

Front. Genet.

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Usher syndrome (USH) is an autosomal recessive (AR) disorder that permanently and severely affects the senses of hearing, vision, and balance. Three clinically distinct types of USH have been identified, decreasing in severity from Type 1 to 3, with symptoms of sensorineural hearing loss (SNHL), retinitis pigmentosa (RP), and vestibular dysfunction. There are currently nine confirmed and two suspected USH-causative genes, and a further three candidate loci have been mapped. The proteins encoded by these genes form complexes that play critical roles in the development and maintenance of cellular structures within the inner ear and retina, which have minimal capacity for repair or regeneration. In the cochlea, stereocilia are located on the apical surface of inner ear hair cells (HC) and are responsible for transducing mechanical stimuli from sound pressure waves into chemical signals. These signals are then detected by the auditory nerve fibers, transmitted to the brain and interpreted as sound. Disease-causing mutations in USH genes can destabilize the tip links that bind the stereocilia to each other, and cause defects in protein trafficking and stereocilia bundle morphology, thereby inhibiting mechanosensory transduction. This review summarizes the current knowledge on Usher syndrome with a particular emphasis on mutations in USH genes, USH protein structures, and functional analyses in animal models. Currently, there is no cure for USH. However, the genetic therapies that are rapidly developing will benefit from this compilation of detailed genetic information to identify the most effective strategies for restoring functional USH proteins.

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“…2 0 1 0 ) . N o l o s s o f mechanotransduction-dependent behaviors was found in zebrafish mutants (Blanco-Sánchez et al 2018), suggesting potential compensation by other GRXCR genes.…”

Section: Zebrafish Genetic Models Of Hearing Lossmentioning

confidence: 99%

Water Waves to Sound Waves: Using Zebrafish to Explore Hair Cell Biology

Pickett

Raible

2019

JARO

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Although perhaps best known for their use in developmental studies, over the last couple of decades, zebrafish have become increasingly popular model organisms for investigating auditory system function and disease. Like mammals, zebrafish possess inner ear mechanosensory hair cells required for hearing, as well as superficial hair cells of the lateral line sensory system, which mediate detection of directional water flow. Complementing mammalian studies, zebrafish have been used to gain significant insights into many facets of hair cell biology, including mechanotransduction and synaptic physiology as well as mechanisms of both hereditary and acquired hair cell dysfunction. Here, we provide an overview of this literature, highlighting some of the particular advantages of using zebrafish to investigate hearing and hearing loss.

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Grxcr1 Promotes Hair Bundle Development by Destabilizing the Physical Interaction between Harmonin and Sans Usher Syndrome Proteins

Cited by 11 publications

References 47 publications

Pregnancy-associated plasma protein-aa regulates endoplasmic reticulum–mitochondria associations

Pregnancy-associated plasma protein-aa regulates endoplasmic reticulum–mitochondria associations

Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy

Water Waves to Sound Waves: Using Zebrafish to Explore Hair Cell Biology

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