PUBLICATION

Activation of Sonic hedgehog signaling in neural progenitor cells promotes glioma development in the zebrafish optic pathway

Authors: Ju, B., Chen, W., Spitsbergen, J.M., Lu, J., Vogel, P., Peters, J.L., Wang, Y.D., Orr, B.A., Wu, J., Henson, H.E., Jia, S., Parupalli, C., Taylor, M.R.
ID: ZDB-PUB-140513-238
Date: 2014
Source: Oncogenesis 3: e96 (Journal)
Registered Authors: Chen, Wenbiao, Spitsbergen, Jan, Taylor, Michael R.
Keywords: none
Datasets: GEO:GSE40761
MeSH Terms: none
PubMed: 24686726 Full text @ Oncogenesis

Abstract

Dysregulation of Sonic hedgehog (Shh) signaling has been implicated in glioma pathogenesis. Yet, the role of this pathway in gliomagenesis remains controversial because of the lack of relevant animal models. Using the cytokeratin 5 promoter, we ectopically expressed a constitutively active zebrafish Smoothened (Smoa1) in neural progenitor cells and analyzed tumorigenic capacity of activated Shh signaling in both transient and stable transgenic fish. Transient transgenic fish overexpressing Smoa1 developed retinal and brain tumors, suggesting smoa1 is oncogenic in the zebrafish central nervous system (CNS). We further established stable transgenic lines that simultaneously developed optic pathway glioma (OPG) and various retinal tumors. In one of these lines, up to 80% of F1 and F2 fish developed tumors within 1 year of age. Microarray analysis of tumor samples showed upregulated expression of genes involved in the cell cycle, cancer signaling and Shh downstream targets ptc1, gli1 and gli2a. Tumors also exhibited specific gene signatures characteristic of radial glia and progenitor cells as transcriptions of radial glia genes cyp19a1b, s100β, blbp, gfap and the stem/progenitor genes nestin and sox2 were significantly upregulated. Overexpression of GFAP, S100β, BLBP and Sox2 was confirmed by immunofluorescence. We also detected overexpression of Mdm2 throughout the optic pathway in fish with OPG, therefore implicating the Mdm2-Tp53 pathway in glioma pathogenesis. In conclusion, we demonstrate that activated Shh signaling initiates tumorigenesis in the zebrafish CNS and provide the first OPG model not associated with neurofibromatosis 1.

Genes / Markers

Marker	Marker Type	Name
cyp19a1b	GENE	cytochrome P450, family 19, subfamily A, polypeptide 1b
fabp7a	GENE	fatty acid binding protein 7, brain, a
gfap	GENE	glial fibrillary acidic protein
gli1	GENE	GLI family zinc finger 1
gli2a	GENE	GLI family zinc finger 2a
krt5	GENE	keratin 5
mib1	GENE	MIB E3 ubiquitin protein ligase 1
nes	GENE	nestin
pax2a	GENE	paired box 2a
s100b	GENE	S100 calcium binding protein, beta (neural)

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Figures

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Expression

Gene	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
EGFP	c264Tg; sj4Tg	standard conditions	Prim-15		brain	IFL	Fig. S2
EGFP	c264Tg; sj4Tg	standard conditions	Day 4		cranial nerve II	IFL	Fig. 2
EGFP	mib1^{hi904Tg/hi904Tg}; sj5Tg	standard conditions	Protruding-mouth	Not Detected	brain	IHC	Fig. 1
EGFP	mib1^{hi904Tg/hi904Tg}; sj5Tg	standard conditions	Protruding-mouth		integument	IHC	Fig. 1
EGFP	mib1^{hi904Tg/hi904Tg}; sj5Tg	standard conditions	Protruding-mouth	Not Detected	retina	IHC	Fig. 1
EGFP	sj4Tg	standard conditions	Prim-5		forebrain	IFL	Fig. 2
EGFP	sj4Tg	standard conditions	Prim-5		optic cup neuroblast	IFL	Fig. 2
EGFP	sj5Tg	standard conditions	Protruding-mouth		brain	IHC	Fig. 1
EGFP	sj5Tg	standard conditions	Protruding-mouth		brain	IFL	Fig. 1
EGFP	sj5Tg	standard conditions	Adult		cranial nerve II astrocyte	IHC	Fig. 1

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
c264Tg; sj4Tg	standard conditions	Day 4	optic furrow closure incomplete, abnormal	Fig. S2
c264Tg; sj4Tg	standard conditions	Days 14-20	retina cell population proliferation increased process quality, abnormal	Fig. S2
c264Tg; sj4Tg	standard conditions	Days 45-89	optic furrow closure incomplete, abnormal	Fig. S2
sj4Tg	standard conditions	Adult	cranial nerve II hyperplastic, abnormal	Fig. 4
sj4Tg	standard conditions	Adult	cranial nerve II increased size, abnormal	Fig. 2
sj4Tg	standard conditions	Adult	cranial nerve II neoplastic, abnormal	Fig. 4
sj4Tg	standard conditions	Adult	eye glioma increased object quality, abnormal	Fig. 4
sj4Tg	standard conditions	Adult	eye glioma increased object quality, abnormal	Fig. 5
sj4Tg	standard conditions	Adult	eye increased pigmentation, abnormal	Fig. 3
sj4Tg	standard conditions	Adult	eye neoplastic, abnormal	Fig. 6

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
c264Tg	Tg(UAS-E1B:NTR-mCherry)	Transgenic Insertion
hi904Tg	Tg(F5)	Transgenic Insertion	mib1
sj4Tg	Tg(krt5:GAL4-VP16,14xUAS:smo-EGFP)	Transgenic Insertion
sj5Tg	Tg2(krt5:EGFP)	Transgenic Insertion

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Human Disease / Model

Human Disease	Fish	Conditions	Evidence
optic nerve glioma	sj4Tg	standard conditions	TAS

Sequence Targeting Reagents

Fish

Fish
c264Tg
c264Tg; sj4Tg
mib1^{hi904Tg/hi904Tg}
mib1^{hi904Tg/hi904Tg}; sj5Tg
sj4Tg
sj5Tg
WT

Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab1-mdm2	polyclonal	mdm2	IgG	Rabbit
Ab1-pax2	polyclonal	pax2a		Rabbit
Ab1-s100	polyclonal	s100b		Rabbit
Ab1-sox2	polyclonal	sox2		Rabbit
Ab2-fabp7	polyclonal			Rabbit
Ab2-gfap	polyclonal	gfap		Rabbit
Ab3-gfap	monoclonal		IgG1	Mouse
Ab5-casp3	polyclonal			Rabbit
Ab18-h3	polyclonal			Rabbit

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Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
GAL4	EFG	GAL4
mCherry	EFG	mCherry
NTR	EFG	NTR

Mapping

Ju et al., 2014 ZDB-PUB-140513-238 PMID:24686726

Activation of Sonic hedgehog signaling in neural progenitor cells promotes glioma development in the zebrafish optic pathway

Ju et al., 2014

ZDB-PUB-140513-238
PMID:24686726