Abstract
AbstractDuring an ENU (N‐ethyl‐N‐nitrosourea) mutagenesis screen, we observed a dominant small‐eye mutant mouse with viable homozygotes (gene symbol Aey69). We determined linkage to mouse chromosome 3 between the markers D3Mit188 and D3Mit11; sequencing demonstrated a 358A‐>C mutation (Ile120Leu) in the Hist2h3c1 gene and a 71T‐>C (Val24Ala) mutation in the Gja8 gene. Analysis of eye development in the homozygous mutants documented an altered lens development starting from the lens vesicle stage including decreasing expression of crystallins and of lens‐specific transcription factors PITX3 and FOXE3. In contrast, we observed an early expression of retinal progenitor cells characterized by BRN3 and OTX2. These changes in the retina happen in parallel with apoptotic processes in the lens vesicle. The excessive retinal hyperproliferation is characterized by an increased level of Ki67. At postnatal stages, all principal retinal cell types are present, when the overgrowing retina fills the entire bulbus. Morpholino‐mediated knock‐down of the hist2h3ca1 gene in zebrafish leads to a specific perturbation of lens development. When injected into zebrafish zygotes, only the mutant mouse mRNA leads to severe malformations (cyclopia to microphthalmia). The wild‐type Hist2h3c1 mRNA can rescue the morpholino‐induced defects corroborating its specific function in lens development. The data highlight the importance of Hist2h3c1 (encoding a canonical H3.2 variant) in the formation of lens and retina.
Highlights
The ocular system presents an interesting challenge in understanding its development
The standardized phenotyping of this mutant line in the German Mouse Clinic (GMC) revealed only a few altered phenotypes between wild types and the homozygous mutants: increased locomotor activity and increased rearing, which was combined with decreased anxiety
Since the microphthalmia was the most severe manifestation of the mutation, we focused in the following experiments on this particular phenotype
Summary
The ocular system presents an interesting challenge in understanding its development. The vertebrate eye comprises tissues from different embryonic origins: the lens and the cornea derive from the surface ectoderm, while the retina, the epithelial layers of the iris and the ciliary body originate from the anterior neural plate. Perturbation of this system can cause isolated or widespread ocular abnormalities including microphthalmia, or even anophthalmia (Plaisancie et al, 2016), that can obstruct the vision at different levels and lead to blindness. A significant number of genes are involved in the control of eye development. The most notable classes include homeobox genes such as Lhx, Otx, Pax, Pitx, Rx and Six (Heavner et al, 2012)
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