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New lessons from mouse mutants for eye and lens development: The role of BMPR1B, FGF9, FGF10 and GJF1.

Vortrag: XIX Biennal Meeting of the International Society for Eye Research (ISER), 18-23 July 2010, Montreal, Canada. (2010)
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Background Phenotype-driven screening of mouse mutations induced by ethylnitrosourea (ENU) leads to the discovery of clinically relevant phenotypes. Methods Offspring of ENU-treated male mice are screened by various techniques for eye and lens abnormalities. Confirmed mutations were characterized by a positional cloning approach. Results The recessive mouse mutant Ali30 was characterized by a shortened axial length and alterations of the optic nerve head; the mutation analysis revealed a point-mutation in intron 10 of the Bmpr1b gene (encoding the bone morphogenic protein receptor 1b) leading to alternative splice products. In contrast to a dominant-negative allele of the Bmpr1b, the lenses of the Ali30 mutants remain fully transparent and regular in size and shape. The dominant mouse mutant Aey17 was characterized by a small-eye phenotype; in contrast to the classical Pax6 mutants, Aey17 mutants are fully viable as homozygotes. Mutation analysis revealed a point mutation in the penultimate base of the first intron of Fgf10 causing aberrant splicing with an additional 49 bp in exon 2, to a frame shift and a premature stop codon after 54 new amino acids. The histological analysis of the major ocular tissues (cornea, lens, retina) did not reveal major alterations as compared to the wild type, but the size of the Harderian gland was remarkably reduced in heterozygotes. The slit-eye phenotype is caused by irritation of the dry eye. The dominant mouse mutant Aca12 is characterized by a smaller lens; the molecular analysis identified a missense mutation in the Fgf9 gene affecting the heparin binding region of the Fgf9 protein. The Aca12 mutation represents a hypomorphic allele. The reduced thickness of the Aca12 lenses suggests a novel function of Fgf9 in regulation of lens fiber development. The reduction of lens size is a result of lens growth retardation starting prenatally and continuing after birth. Fgf9Y162C lenses remain transparent at early stages but develop polar cataracts at the age of one year. The dominant small-eye mutant Aey12 is characterized by impaired primary lens fiber cell elongation. Mutation analysis revealed a point mutation in the Gjf1 gene encoding a connexin-like protein. The gene is expressed in the posterior part of the lens vesicle, where the primary fiber elongation starts. The mutation alters the expression pattern of Pax6, Prox1, Six3 and Crygd. Conclusions Fgf10 and Bmpr1b have no influence on lens development, but we demonstrated the importance of Gjf1 on primary and of Fgf9 on secondary lens fiber growth.
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Publikationstyp Sonstiges: Vortrag
Konferenztitel XIX Biennal Meeting of the International Society for Eye Research (ISER)
Konferzenzdatum 18-23 July 2010
Konferenzort Montreal, Canada