Splice‐site mutation in the Bmpr1b gene of the mouse causes optic nerve head dysgenesis and retinal gliosis

Abstract

PurposeA novel splice‐site mutation of the Bmpr1b gene was characterized in offspring of N‐ethyl‐N‐nitrosourea (ENU) ‐treated mice; besides irregular limb morphology the mutants show an enlarged optic nerve head.MethodsEye development of Bmpr1b mutants was analyzed for Bmp signalling via SMAD1 and 5, and for the expression of PAX2 as a transcription factor important for proper optic nerve head development.ResultsBMP signalling indicated by the presence of phosphorylated SMAD1 and 5 was first observed in a few regions of the developing lens capsule and of the developing retina of mouse embryos at day 11.5 after fertilization. At this stage, no differences in SMAD1/5 phosphorylation have been observed between wild‐type mice and the mutants. However, at the end of embryonic development (E17.5) and in the first days after birth (P7), higher concentrations of phosphorylated SMAD1/5 proteins are found at the optic nerve head region, whereas in the Bmpr1b mutants, the BMP signalling is dramatically reduced indicated by a significant loss of pSMAD1/5 staining. The clear reduction of the pSMAD1/5 in heterozygous and homozygous Bmpr1b mutants leads to a stronger optic disc cupping and to the formation of retinal gliosis indicated by the presence of disorganized and activated astrocytes. Loss of BMP‐mediated signalling in the Bmpr1b mouse mutants is also accompanied by a decrease of Pax2 expression at the optic nerve head region towards the end of embryonic development resulting in an additional line of arguments for the rather specific effect at the optic nerve head.ConclusionsThe T‐G mutation in the splice donor site of exon 10 of the Bmpr1b gene leads to retinal gliosis and hypoplasia of the optic nerve head, which is mainly caused by the repression of BMP‐mediated signalling.