Mutation in the mouse histone gene Hist2h3c1 leads to degeneration of the lens vesicle and severe microphthalmia

During 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.