Defects in eye development in transgenic mice overexpressing the heparan sulfate proteoglycan agrin

Peter G Fuerst; Steven M Rauch; Robert W Burgess

doi:10.1016/j.ydbio.2006.11.033

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Defects in eye development in transgenic mice overexpressing the heparan sulfate proteoglycan agrin

Journal article

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Defects in eye development in transgenic mice overexpressing the heparan sulfate proteoglycan agrin

Peter G Fuerst, Steven M Rauch and Robert W Burgess

Developmental biology, Vol.303(1), pp.165-180

03/01/2007

DOI: https://doi.org/10.1016/j.ydbio.2006.11.033

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https://hdl.handle.net/2376/114097

PMCID: PMC1831846

PMID: 17196957

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https://doi.org/10.1016/j.ydbio.2006.11.033View

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Abstract

Immunohistochemistry

Homeodomain Proteins - metabolism

Eye Abnormalities - embryology

Visual Pathways - metabolism

Extracellular Matrix - metabolism

Hedgehog Proteins - metabolism

Gene Expression Profiling

Agrin - metabolism

Visual Pathways - embryology

Eye Abnormalities - metabolism

Repressor Proteins - metabolism

Agrin - genetics

Mice, Inbred C57BL

Transgenes - genetics

Mice, Transgenic

PAX6 Transcription Factor

DNA Primers

Eye Abnormalities - genetics

Blotting, Western

Animals

Eye Proteins - metabolism

Heparan Sulfate Proteoglycans - metabolism

Mice

Paired Box Transcription Factors - metabolism

Quantitative Trait Loci - genetics

The importance of heparan sulfate proteoglycans (HSPGs) in neurodevelopment is becoming increasingly clear. However, studies on HSPGs are hampered by pleiotropic effects when synthesis or modification of heparan sulfate itself is targeted, and by redundancy when the core proteins are altered. Gain-of-function experiments can sometimes circumvent these issues. Here we establish that transgenic mice overexpressing the HSPG agrin have severe ocular dysgenesis. The defects occur through a gain-of-function mechanism and penetrance is dependent on agrin dosage. The agrin-induced developmental defects are highly variable, and include anophthalmia, persistence of vitreous vessels, and fusion of anterior chamber structures. A frequently observed defect is an optic stalk coloboma leading to the misdifferentiation of the optic stalk as retina, which becomes continuous with the forebrain. The defects in optic-stalk differentiation correlate with reduced sonic hedgehog immunoreactivity and overexpansion of the PAX6 domain from the retina into the optic stalk. The ocular phenotypes associated with agrin overexpression are dependent on genetic background, occurring with high penetrance in inbred C57BL/6J mice. Distinct loci sensitizing C57BL/6J mice to agrin-induced dysgenesis were identified. These results indicate that agrin overexpression will provide a tool to explore the molecular interactions of the extracellular matrix and cell surface in eye development, and provide a means for identifying modifier loci that sensitize mice to developmental eye defects.

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Title: Defects in eye development in transgenic mice overexpressing the heparan sulfate proteoglycan agrin
Creators: Peter G Fuerst - The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
Steven M Rauch
Robert W Burgess
Publication Details: Developmental biology, Vol.303(1), pp.165-180
Academic Unit: Center for Reproductive Biology
Publisher: United States
Grant note: P30 CA034196 / NCI NIH HHS R03 EY016031 / NEI NIH HHS F32 EY015966 / NEI NIH HHS CA 34196 / NCI NIH HHS EY 016031 / NEI NIH HHS EY 15966 / NEI NIH HHS
Identifiers: 99900547663501842
Language: English
Resource Type: Journal article