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. 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 morphological 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. Only Crx E80A/+ retinae elaborate rod outer segments but still lose visual function by young adulthood. The presence of irregular retinal rosettes displaces 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, secondarily impairing the localization of inner neurons and vasculature. A deeper understanding of these cellular underpinnings will inform pathogenesis of CRX homeodomain mutations.