Aberrant retinal structure and vasculature in mouse models of dominant retinopathies caused by CRX homeodomain mutations.

CRX is a transcription factor essential for photoreceptor differentiation and functional development. Two missense mutations in CRX homeodomain, CRX (E80A) and CRX (K88N) , are linked to early-onset dominant retinopathies. Molecular studies have revealed distinct profiles of perturbed gene expression in differentiating photoreceptors of knock-in mouse models, resulting from altered DNA binding activities of mutant CRX proteins. This study characterizes concurrent retinal and vascular alterations in knock-in mouse models. Fated cones are present in heterozygous and homozygous Crx (E80A) and Crx (K88N) mutants at birth, but subsequent cone differentiation is rapidly compromised. Expression of rod marker rhodopsin (RHO) is absent in Crx (K88N/N) retinae but present in other mutants through adulthood. Notably, as compared to wildtype controls, RHO expression is prematurely activated in neonatal Crx (E80A) mutants. Among tested mutants, only Crx (E80A/+) retinae elaborate rod outer segments but still lose visual function by young adulthood. The presence of irregular retinal rosettes is a striking pathological phenotype in all mutants. Retinal rosettes displace the localization of inner neurons without affecting their cell numbers during retinal development. Retinal vessels develop close contact with rosette structures. In summary, disrupted photoreceptor differentiation leads to the loss of visual function and formation of retinal rosettes. The presence of retinal rosettes secondarily impairs the localization of inner neurons and vasculature. A deeper understanding of these cellular underpinnings will inform pathogenesis of CRX homeodomain mutations.