PUBLICATION

Complexes of Usher proteins preassemble at the endoplasmic reticulum and are required for trafficking and ER homeostasis

Authors

Blanco-Sánchez, B., Clément, A., Fierro, J., Washbourne, P., Westerfield, M.

ID

ZDB-PUB-140513-359

Date

2014

Source

Disease models & mechanisms 7: 547-59 (Journal)

Registered Authors

Blanco, Bernardo, Clément, Aurélie, Washbourne, Philip, Westerfield, Monte

Keywords

Cadherin23, ER stress, Hair cell, Harmonin, Ift88, Myo7aa, Trafficking, Usher syndrome, Zebrafish

MeSH Terms

Hair Cells, Auditory, Inner
Protein Transport
Zebrafish Proteins/genetics
Zebrafish Proteins/metabolism*
Endoplasmic Reticulum Stress
Mutation/genetics
Protein Binding
Endoplasmic Reticulum/metabolism*
Transport Vesicles/metabolism
Subcellular Fractions/metabolism
Homeostasis*
Zebrafish/metabolism*
Adaptor Proteins, Signal Transducing/genetics
Adaptor Proteins, Signal Transducing/metabolism*
Animals
Mechanoreceptors/metabolism
Multiprotein Complexes/metabolism*

(all 17)

PubMed

24626987 Full text @ Dis. Model. Mech.

Abstract

Usher syndrome (USH), the leading cause of hereditary combined hearing and vision loss, is characterized by sensorineural deafness and progressive retinal degeneration. Mutations in several different genes produce USH, but the proximal cause of sensory cell death remains mysterious. We adapted a proximity ligation assay to analyze associations among three of the USH proteins, Cdh23, Harmonin and Myo7aa, and the microtubule-based transporter Ift88 in zebrafish inner ear mechanosensory hair cells. We found that the proteins are in close enough proximity to form complexes and that these complexes preassemble at the endoplasmic reticulum (ER). Defects in any one of the three USH proteins disrupt formation and trafficking of the complex and result in diminished levels of the other proteins, generalized trafficking defects and ER stress that triggers apoptosis. ER stress, thus, contributes to sensory hair cell loss and provides a new target to explore for protective therapies for USH.

Genes / Markers

Figures

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Expression

Gene	Antibody	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
adgrv1		cdh23^tj264/tj264	standard conditions	Day 5	Not Detected	hair cell	IHC	Fig. 7
adgrv1		ift88^tz288/tz288	standard conditions	Day 5		hair cell	IHC	Fig. 7
adgrv1		myo7aa^ty220/ty220	standard conditions	Day 5		hair cell	IHC	Fig. 7
adgrv1		ush1c^fh293/fh293	standard conditions	Day 5		hair cell	IHC	Fig. 7
adgrv1		WT	standard conditions	Day 5		hair cell	IHC	Fig. 7
ift88	ab1-ift88	cdh23^tj264/tj264	standard conditions	Day 5		hair cell	IHC	Fig. 2
ift88	ab1-ift88	ift88^tz288/tz288	standard conditions	Day 5	Not Detected	hair cell	IHC	Fig. 2
ift88	ab1-ift88	myo7aa^ty220/ty220	standard conditions	Day 5		hair cell	IHC	Fig. 2
ift88	ab1-ift88	ush1c^fh293/fh293	standard conditions	Day 5		hair cell	IHC	Fig. 2
ift88	ab1-ift88	WT	standard conditions	Day 5		hair cell kinocilium	IHC	Fig. 1

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
cdh23^tj264/tj264	standard conditions	Day 5	anterior macula stereocilium bundle bent, abnormal	Fig. 1
cdh23^tj264/tj264	standard conditions	Day 5	anterior macula stereocilium bundle splayed, abnormal	Fig. 1
cdh23^tj264/tj264	standard conditions	Day 5	hair cell anterior macula apoptotic process increased occurrence, abnormal	Fig. 1
cdh23^tj264/tj264	standard conditions	Day 5	hair cell anterior macula epithelium organization quality, normal	Fig. 1
cdh23^tj264/tj264	standard conditions	Day 5	hair cell anterior macula normal amount, normal	Fig. 1
cdh23^tj264/tj264	standard conditions	Day 5	hair cell anterior macula stereocilium decreased amount, abnormal	Fig. 1
ift88^tz288/tz288	standard conditions	Day 5	anterior macula stereocilium bundle bent, abnormal	Fig. 1
ift88^tz288/tz288	standard conditions	Day 5	anterior macula stereocilium bundle splayed, abnormal	Fig. 1
ift88^tz288/tz288	standard conditions	Day 5	hair cell anterior macula apoptotic process increased occurrence, abnormal	Fig. 1
ift88^tz288/tz288	standard conditions	Day 5	hair cell anterior macula epithelium organization quality, normal	Fig. 1

1 - 10 of 18

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Mutations / Transgenics

Allele	Type	Affected Genomic Region
fh293	Point Mutation	ush1c
tj264	Point Mutation	cdh23
ty220	Point Mutation	myo7aa
tz288	Point Mutation	ift88

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
cdh23	MO1-cdh23	MRPHLNO
cdk5	MO3-cdk5	MRPHLNO

Fish

Fish
cdh23^tj264/tj264
ift88^tz288/tz288
myo7aa^ty220/ty220
ush1c^fh293/fh293
WT

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Blanco-Sánchez et al., 2014 ZDB-PUB-140513-359 PMID:24626987

Complexes of Usher proteins preassemble at the endoplasmic reticulum and are required for trafficking and ER homeostasis

Blanco-Sánchez et al., 2014

ZDB-PUB-140513-359
PMID:24626987