PUBLICATION

Usher syndrome Type 1-associated gene, pcdh15b, is required for photoreceptor structural integrity in zebrafish

Authors

Miles, A., Blair, C., Emili, A., Tropepe, V.

ID

ZDB-PUB-211022-44

Date

2021

Source

Disease models & mechanisms 14(12): (Journal)

Registered Authors

Tropepe, Vincent

Keywords

Calyceal processes, Outer segment, Photoreceptor, Retina, Usher Syndrome, Zebrafish

MeSH Terms

Mice
Humans
Retinal Degeneration*/genetics
Zebrafish/genetics
Zebrafish/metabolism
Usher Syndromes*/genetics
Disease Models, Animal
Animals

(all 8)

PubMed

34668518 Full text @ Dis. Model. Mech.

Abstract

Blindness associated with Usher Syndrome Type 1 (USH1) is typically characterized as rod photoreceptor degeneration, followed by secondary loss of cones. The mechanisms leading to blindness are unknown since most genetic mouse models only recapitulate auditory defects. We generated zebrafish mutants for one of the USH1 proteins, protocadherin-15b (pcdh15b), a putative cell adhesion molecule. Zebrafish pcdh15 is expressed exclusively in photoreceptors within calyceal processes (CPs), at the base of the outer segment (OS), and within the synapse. In our mutants, rod and cone photoreceptor integrity is compromised with early and progressively worsening abnormal OS disc growth and detachment, in part due to weakening CP contacts. These effects were attenuated or exacerbated by growth in dark and bright light conditions, respectively. We also describe novel evidence for structural defects in synapses of pcdh15 mutant photoreceptors. Cell death does not accompany these defects at early stages, suggesting that photoreceptor structural defects, rather than overt cell loss, may underlie vision deficits. Thus, we present the first genetic animal model of a pcdh15-associated retinopathy that can be used to understand the etiology of blindness in USH1.

Genes / Markers

Figures

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB	high light intensity	Days 7-13	photoreceptor outer segment layer microvillus attached to photoreceptor outer segment layer photoreceptor outer segment, normal	Fig. 7.
AB	high light intensity	Days 7-13	photoreceptor outer segment layer photoreceptor outer segment morphology, normal	Fig. 7.
AB	constant dark	Days 7-13	photoreceptor outer segment layer microvillus attached to photoreceptor outer segment layer photoreceptor outer segment, normal	Fig. 7.
AB	constant dark	Days 7-13	photoreceptor outer segment layer photoreceptor outer segment morphology, normal	Fig. 7.
pcdh15b^uot14/uot14	standard conditions	Day 4	eye photoreceptor cell photoreceptor outer segment detached from eye photoreceptor cell photoreceptor inner segment, abnormal	Fig. 6.
pcdh15b^uot14/uot14	standard conditions	Day 4	photoreceptor outer segment layer microvillus attached to photoreceptor outer segment layer photoreceptor outer segment, normal	Fig. 3.
pcdh15b^uot14/uot14	standard conditions	Day 4	photoreceptor outer segment layer photoreceptor outer segment malformed, abnormal	Fig. 6.
pcdh15b^uot14/uot14	standard conditions	Day 5	eye photoreceptor cell photoreceptor outer segment detached from eye photoreceptor cell cell body, abnormal	Fig. 5.
pcdh15b^uot14/uot14	standard conditions	Day 5	eye photoreceptor cell photoreceptor outer segment detached from eye photoreceptor cell photoreceptor inner segment, abnormal	Fig. 5.
pcdh15b^uot14/uot14	standard conditions	Day 5	photoreceptor outer segment layer photoreceptor disc membrane malformed, abnormal	Fig. 4.

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
uot14		Small Deletion	pcdh15b
uot15		Insertion	pcdh15b

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
Usher syndrome type 1F	pcdh15b^uot14/uot14	standard conditions	TAS
Usher syndrome type 1F	pcdh15b^uot15/uot15	standard conditions	TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
pcdh15b	CRISPR3-pcdh15b	CRISPR

Fish

Fish
AB
pcdh15b^uot14/uot14
pcdh15b^uot15/uot15

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Miles et al., 2021 ZDB-PUB-211022-44 PMID:34668518

Usher syndrome Type 1-associated gene, pcdh15b, is required for photoreceptor structural integrity in zebrafish

Miles et al., 2021

ZDB-PUB-211022-44
PMID:34668518