PUBLICATION

Wolfram syndrome 1b mutation suppresses Mauthner-cell axon regeneration via ER stress signal pathway

Authors

Wang, Z., Wang, X., Shi, L., Cai, Y., Hu, B.

ID

ZDB-PUB-221218-6

Date

2022

Source

Acta neuropathologica communications 10: 184184 (Journal)

Registered Authors

Hu, Bing

Keywords

ER stress, Mauthner cell, Regeneration, Zebrafish, wfs1b

MeSH Terms

Zebrafish/metabolism
Endoplasmic Reticulum Stress
Membrane Proteins/genetics
Membrane Proteins/metabolism
Axons/metabolism
Animals
Mutation/genetics
Wolfram Syndrome*/genetics
Wolfram Syndrome*/metabolism
Signal Transduction
Humans
Nerve Regeneration

(all 12)

PubMed

36527091 Full text @ Acta Neuropathol Commun

Abstract

Wolfram Syndrome (WS) is a fatal human inherited disease with symptoms of diabetes, vision decreasing, and neurodegeneration caused by mutations in the endoplasmic reticulum (ER)-resident protein WFS1. WFS1 has been reported to play an important role in glucose metabolism. However, the role of WFS1 in axonal regeneration in the central nervous system has so far remained elusive. Herein, we established a model of the wfs1b globally deficient zebrafish line. wfs1b deficiency severely impeded the Mauthner-cell (M-cell) axon regeneration, which was partly dependent on the ER stress response. The administration of ER stress inhibitor 4-Phenylbutyric acid (4-PBA) promoted M-cell axon regeneration in wfs1b^-/- zebrafish larvae, while the ER stress activator Tunicamycin (TM) inhibited M-cell axon regeneration in wfs1b^+/+ zebrafish larvae. Moreover, complementation of wfs1b at the single-cell level stimulated M-cell axon regeneration in the wfs1b^-/- zebrafish larvae. Altogether, our results revealed that wfs1b promotes M-cell axon regeneration through the ER stress signal pathway and provide new evidence for a therapeutic target for WS and axon degeneration.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
atf4a	wfs1b^ah828/ah828	standard conditions	Day 6	whole organism	RTPCR	Fig. 6
atf4a	WT	standard conditions	Day 6	whole organism	RTPCR	Fig. 6
atf6	wfs1b^ah828/ah828	standard conditions	Day 6	whole organism	RTPCR	Fig. 6
atf6	wfs1b^ah828/ah828; zf206Et	control	Days 7-13	whole organism	RTPCR	Fig. 7
atf6	wfs1b^ah828/ah828; zf206Et	light ablation: axon: Mauthner neuron, chemical treatment by environment: tunicamycin	Days 7-13	whole organism	RTPCR	Fig. 7
atf6	wfs1b^ah828/ah828; zf206Et	light ablation: axon: Mauthner neuron, chemical treatment by environment: 4-phenylbutyric acid	Days 7-13	whole organism	RTPCR	Fig. 7
atf6	WT	standard conditions	Day 6	whole organism	RTPCR	Fig. 6
atf6	zf206Et	light ablation: axon: Mauthner neuron, chemical treatment by environment: tunicamycin	Days 7-13	whole organism	RTPCR	Fig. 7
atf6	zf206Et	control	Days 7-13	whole organism	RTPCR	Fig. 7
EGFP	wfs1b^ah828/ah828; zf206Et	light ablation: axon: Mauthner neuron	Days 7-13	Mauthner neuron axon	IFL	Fig. 3

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
wfs1b^ah828/+	standard conditions	Day 6	brain endoplasmic reticulum decreased diameter, abnormal	Fig. 6
wfs1b^ah828/+	standard conditions	Day 6	brain endoplasmic reticulum decreased perimeter, abnormal	Fig. 6
wfs1b^ah828/+	standard conditions	Day 6	brain endoplasmic reticulum structure, abnormal	Fig. 6
wfs1b^ah828/ah828	standard conditions	Day 6	brain endoplasmic reticulum decreased diameter, abnormal	Fig. 6
wfs1b^ah828/ah828	standard conditions	Day 6	brain endoplasmic reticulum decreased perimeter, abnormal	Fig. 6
wfs1b^ah828/ah828	standard conditions	Day 6	brain endoplasmic reticulum structure, abnormal	Fig. 6
wfs1b^ah828/ah828	standard conditions	Day 6	whole organism atf4a expression increased amount, abnormal	Fig. 6
wfs1b^ah828/ah828	standard conditions	Day 6	whole organism atf6 expression increased amount, abnormal	Fig. 6
wfs1b^ah828/ah828	standard conditions	Day 6	whole organism hsp90b1 expression increased amount, abnormal	Fig. 6
wfs1b^ah828/ah828	standard conditions	Day 6	whole organism hspa5 expression increased amount, abnormal	Fig. 6

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ah828		Small Deletion	wfs1b
zf206Et	Et(T2KHG)	Transgenic Insertion

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
Wolfram syndrome			TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
wfs1b	CRISPR4-wfs1b	CRISPR

Fish

Fish
wfs1b^ah828/ah828
wfs1b^ah828/ah828; zf206Et
wfs1b^ah828/+
wfs1b^ah828/+; zf206Et
WT
zf206Et

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP

Mapping

Wang et al., 2022 ZDB-PUB-221218-6 PMID:36527091

Wolfram syndrome 1b mutation suppresses Mauthner-cell axon regeneration via ER stress signal pathway

Wang et al., 2022

ZDB-PUB-221218-6
PMID:36527091