PUBLICATION

Loss of cftr function leads to pancreatic destruction in larval zebrafish

Authors

Navis, A., Bagnat, M.

ID

ZDB-PUB-150117-5

Date

2015

Source

Developmental Biology 399(2): 237-48 (Journal)

Registered Authors

Bagnat, Michel

Keywords

Cftr, Cystic fibrosis, Pancreas

MeSH Terms

Chromosomes, Artificial, Bacterial
Cystic Fibrosis Transmembrane Conductance Regulator/genetics
Cystic Fibrosis Transmembrane Conductance Regulator/metabolism*
Cystic Fibrosis/genetics*
Cystic Fibrosis/physiopathology
In Situ Hybridization
Acinar Cells/pathology
Zebrafish/genetics*
Zebrafish/growth & development*
Animals
Disease Models, Animal*
Pancreatic Ducts/cytology
Pancreas/growth & development
Pancreas/pathology*
Fluorescent Antibody Technique
Body Weights and Measures
DNA Primers/genetics
Animals, Genetically Modified
Larva/growth & development

(all 19)

PubMed

25592226 Full text @ Dev. Biol.

Abstract

The development and function of many internal organs requires precisely regulated fluid secretion. A key regulator of vertebrate fluid secretion is an anion channel, the cystic fibrosis transmembrane conductance regulator (CFTR). Loss of CFTR function leads to defects in fluid transport and cystic fibrosis (CF), a complex disease characterized by a loss of fluid secretion and mucus buildup in many organs including the lungs, liver, and pancreas. Several animal models including mouse, ferret and pig have been generated to investigate the pathophysiology of CF. However, these models have limited accessibility to early processes in the development of CF and are not amenable for forward genetic or chemical screens. Here, we show that Cftr is expressed and localized to the apical membrane of the zebrafish pancreatic duct and that loss of cftr function leads to destruction of the exocrine pancreas and a cystic fibrosis phenotype that mirrors human disease. Our analyses reveal that the cftr mutant pancreas initially develops normally, then rapidly loses pancreatic tissue during larval life, reflecting pancreatic disease in CF. Altogether, we demonstrate that the cftr mutant zebrafish is a powerful new model for pancreatitis and pancreatic destruction in CF. This accessible model will allow more detailed investigation into the mechanisms that drive CF of the pancreas and facilitate development of new therapies to treat the disease.

Genes / Markers

Figures

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
cftr^{pd1049/pd1049} (AB)	standard conditions	Protruding-mouth to Days 14-20	primary islet pancreatic B cell amount, normal	Fig. 3
cftr^{pd1049/pd1049} (AB)	standard conditions	Day 5	pancreas development process quality, normal	Fig. 3
cftr^{pd1049/pd1049} (AB)	standard conditions	Day 5	pancreatic duct lumenized, normal	Fig. 3
cftr^{pd1049/pd1049} (AB)	standard conditions	Days 14-20	secondary islet amount, normal	Fig. 3
cftr^{pd1049/pd1049} (AB)	standard conditions	Days 14-20	secondary islet pancreatic B cell amount, normal	Fig. 3
cftr^{pd1049/pd1049} (AB)	standard conditions	Adult	exocrine pancreas central region lacks all parts of type pancreatic acinar cell, abnormal	Fig. 5
cftr^{pd1049/pd1049} (AB)	standard conditions	Adult	exocrine pancreas fibrillary, abnormal	Fig. 5
cftr^{pd1049/pd1049} (AB)	standard conditions	Adult	pancreas degenerate, abnormal	Fig. 5
cftr^{pd1049/pd1049} (AB)	standard conditions	Adult	pancreatic duct dilated, abnormal	Fig. 5
cftr^{pd1049/pd1049} (AB)	standard conditions	Adult	pancreatic duct obstructed, abnormal	Fig. 5

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
gz15Tg	Tg(ela3l:EGFP) Tg(fabp10a:DsRed)	Transgenic Insertion
jh1Tg	Tg(ptf1a:EGFP)	Transgenic Insertion
jh16Tg	TgBAC(ptf1a:GAL4-VP16)	Transgenic Insertion
m1018Tg	Tg(ins:DsRed)	Transgenic Insertion
nkuasgfp1aTg	Tg(5xUAS:EGFP)	Transgenic Insertion
nz50Tg	Tg(lyz:DsRed2)	Transgenic Insertion
pd1041Tg	TgBAC(cftr-GFP)	Transgenic Insertion
pd1042Tg	TgBAC(cftr-RFP)	Transgenic Insertion
pd1049		Indel	cftr
pd1101Tg	TgBAC(cftr:GAL4)	Transgenic Insertion

1 - 10 of 10

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Human Disease / Model

Human Disease	Fish	Conditions	Evidence
cystic fibrosis			TAS

Sequence Targeting Reagents

Fish

Fish
AB
cftr^{pd1049/pd1049} (AB)
cftr^{pd1049/pd1049}; gz15Tg
cftr^{pd1049/pd1049}; gz15Tg; m1018Tg
cftr^{pd1049/pd1049}; jh1Tg
cftr^{pd1049/pd1049}; nz50Tg
gz15Tg
gz15Tg; m1018Tg
gz15Tg; pd1042Tg
jh1Tg

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Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed	EFG	DsRed
DsRed2	EFG	DsRed2
EGFP	EFG	EGFP
GAL4	EFG	GAL4
GFP	EFG	GFP
RFP	EFG	RFP

Mapping

Navis et al., 2015 ZDB-PUB-150117-5 PMID:25592226

Loss of cftr function leads to pancreatic destruction in larval zebrafish

Navis et al., 2015

ZDB-PUB-150117-5
PMID:25592226