PUBLICATION

Zebrafish mutations in gart and paics identify crucial roles for de novo purine synthesis in vertebrate pigmentation and ocular development

Authors

Ng, A., Uribe, R.A., Yieh, L., Nuckels, R., and Gross, J.M.

ID

ZDB-PUB-090706-19

Date

2009

Source

Development (Cambridge, England) 136(15): 2601-2611 (Journal)

Registered Authors

Gross, Jeffrey, Ng, Anthony, Nuckels, Richard, Uribe, Rosa

Keywords

De novo purine synthesis, Microphthalmia, Pigmentation, Zebrafish

MeSH Terms

Adenosine Triphosphate/metabolism
Animals
Apoptosis
Carboxy-Lyases/genetics*
Carboxy-Lyases/metabolism
Cell Proliferation
Embryo, Nonmammalian/metabolism
Embryo, Nonmammalian/pathology
Embryo, Nonmammalian/ultrastructure
Embryonic Development
Eye/embryology*
Eye/pathology
Eye/ultrastructure
Female
Gene Expression Regulation, Developmental
Guanosine Triphosphate/metabolism
Inosine Monophosphate/metabolism
Microphthalmos/genetics
Microphthalmos/pathology
Models, Biological
Mutation/genetics*
Peptide Synthases/genetics*
Peptide Synthases/metabolism
Phenotype
Phosphoribosylglycinamide Formyltransferase/genetics*
Phosphoribosylglycinamide Formyltransferase/metabolism
Pigmentation/genetics*
Pigments, Biological/biosynthesis
Purines/biosynthesis*
Retina/cytology
Retina/ultrastructure
S Phase
Zebrafish/embryology*
Zebrafish/genetics
Zebrafish Proteins/genetics*
Zebrafish Proteins/metabolism

(all 36)

PubMed

19570845 Full text @ Development

Abstract

Although purines and purinergic signaling are crucial for numerous biochemical and cellular processes, their functions during vertebrate embryonic development have not been well characterized. We analyze two recessive zebrafish mutations that affect de novo purine synthesis, gart and paics. gart encodes phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazole synthetase, a trifunctional enzyme that catalyzes steps 2, 3 and 5 of inosine monophosphate (IMP) synthesis. paics encodes phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase, a bifunctional enzyme that catalyzes steps 6 and 7 of this process. Zygotic gart and paics mutants have pigmentation defects in which xanthophore and iridophore pigmentation is almost completely absent, and melanin-derived pigmentation is significantly decreased, even though pigment cells are present in normal amounts and distributions. Zygotic gart and paics mutants are also microphthalmic, resulting from defects in cell cycle exit of proliferative retinoblasts within the developing eye. Maternal-zygotic and maternal-effect mutants demonstrate a crucial requirement for maternally derived gart and paics; these mutants show more severe developmental defects than their zygotic counterparts. Pigmentation and eye growth phenotypes in zygotic gart and paics mutants can be ascribed to separable biosynthetic pathways: pigmentation defects and microphthalmia result from deficiencies in a GTP synthesis pathway and an ATP synthesis pathway, respectively. In the absence of ATP pathway activity, S phase of proliferative retinoblasts is prolonged and cell cycle exit is compromised, which results in microphthalmia. These results demonstrate crucial maternal and zygotic requirements for de novo purine synthesis during vertebrate embryonic development, and identify independent functions for ATP and GTP pathways in mediating eye growth and pigmentation, respectively.

Genes / Markers

Marker	Marker Type	Name
adssl	GENE	adenylosuccinate synthase, like
ccnb1	GENE	cyclin B1
ccnd1	GENE	cyclin D1
dct	GENE	dopachrome tautomerase
gart	GENE	phosphoribosylglycinamide formyltransferase
gch2	GENE	GTP cyclohydrolase 2
gmps	GENE	guanine monophosphate synthase
paics	GENE	phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase
xdh	GENE	xanthine dehydrogenase

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Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
ccnb1	AB	control	Long-pec	retina	ISH	Fig. 10
ccnb1	AB + MO1-adssl	standard conditions	Long-pec	retina	ISH	Fig. 10
ccnd1	AB	control	Long-pec	ciliary marginal zone	ISH	Fig. 10
ccnd1	AB + MO1-adssl	standard conditions	Long-pec	retina	ISH	Fig. 10
gart	WT	standard conditions	Prim-5	whole organism	RTPCR	Fig. 6
gart	WT	standard conditions	Day 6	whole organism	RTPCR	Fig. 6
gart	WT	standard conditions	Protruding-mouth	whole organism	RTPCR	Fig. 6
paics	WT	standard conditions	Prim-5	whole organism	RTPCR	Fig. 6
paics	WT	standard conditions	Day 6	whole organism	RTPCR	Fig. 6
paics	WT	standard conditions	Protruding-mouth	whole organism	RTPCR	Fig. 6

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB + MO1-adssl	standard conditions	Long-pec	S phase increased duration, abnormal	Fig. 10
AB + MO1-adssl	standard conditions	Protruding-mouth	eye decreased size, abnormal	Fig. 9
AB + MO1-adssl	standard conditions	Protruding-mouth	pigmentation occurrence, normal	Fig. 9
AB + MO1-adssl	standard conditions	Protruding-mouth	S phase increased duration, abnormal	Fig. 10
AB + MO1-gmps	standard conditions	Prim-25	melanocyte pigment granule decreased amount, abnormal	text only
AB + MO1-gmps	standard conditions	Protruding-mouth	iridophore pigment granule decreased amount, abnormal	Fig. 9
AB + MO1-gmps	standard conditions	Protruding-mouth	pigmentation disrupted, abnormal	Fig. 9
AB + MO1-gmps	standard conditions	Protruding-mouth	xanthophore pigment granule decreased amount, abnormal	Fig. 9
AB + MO1-gmps	standard conditions	Protruding-mouth	xanthophore present, normal	Fig. 9
gart^{hi3526bTg/hi3526bTg}	control	Long-pec	apoptotic process occurrence, normal	Fig. 8

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
hi2688Tg	Tg(nLacz-GTvirus)	Transgenic Insertion	paics
hi3081Tg	Tg(nLacz-GTvirus)	Transgenic Insertion	adssl
hi3526bTg	Tg(nLacz-GTvirus)	Transgenic Insertion	gart

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
adssl	MO1-adssl	MRPHLNO
gmps	MO1-gmps	MRPHLNO

Fish

Fish
AB
AB + MO1-adssl
AB + MO1-gmps
adssl^hi3081Tg
gart^{hi3526bTg/hi3526bTg}
gart^{hi3526bTg/hi3526bTg}
gart^{hi3526bTg/hi3526bTg}
paics^{hi2688Tg/hi2688Tg}
paics^{hi2688Tg/hi2688Tg}
paics^{hi2688Tg/hi2688Tg}

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Antibodies

Orthology

Engineered Foreign Genes

Mapping

Ng et al., 2009 ZDB-PUB-090706-19 PMID:19570845

Zebrafish mutations in gart and paics identify crucial roles for de novo purine synthesis in vertebrate pigmentation and ocular development

Ng et al., 2009

ZDB-PUB-090706-19
PMID:19570845