Ambati et al. reply:

We thank Sengupta and Caballero for their interest in our work. Although a small fraction of Bst+/− mice spontaneously develop choroidal neovascularization (CNV), Sengupta and Caballero do not mention that a majority of these heterozygous mice show many other severe ocular disturbances1,2,3. Nearly 60% of Bst+/− mice have abnormal pupillary light responses owing to unilateral or bilateral atrophy of the optic nerves. The mean number of retinal ganglion cells is reduced by 70% as a result of delayed fusion of the optic fissure. In addition to optic nerve malformation (coloboma), several foci of the neural retina are characterized by folds, dysplasia and thinning. Ectopic ganglion cell axons and photoreceptor nuclei are further examples of disorganization. Persistence of the hyaloid vessels is another ocular disturbance in Bst+/− mice.

Although the optic nerve pathology in Bst+/− mice is vaguely reminiscent of autosomal dominant optic atrophy (DOA) in humans, it also includes numerous other ocular abnormalities not resembling those seen in DOA. In addition, the mouse ortholog of the human OPA1 gene, which is mutated in DOA, has been excluded from the mouse Bst locus4. Given that the CNV phenotype in Bst+/− mice is even more distant than the optic nerve abnormality from the respective human conditions, CNV in these mice is likely to be as uninstructive about the pathogenesis of the human condition as, say, the appearance of lens opacities in these mice is to be about age-related cataract in patients. The ocular phenotype of patients with early or late AMD bears no resemblance to the panoply of structural abnormalities in Bst+/− mice, which probably result from global embryonic dysfunction rather than specific perturbations of cellular pathways. Nevertheless, given the rare occurrence of spontaneous CNV in mice, study of this angiogenic process will provide insight into the secondary effects of CNV on photoreceptor disruption, which ultimately leads to deficits in visual perception.

See “Mouse models of visual deficits” by Sengupta & Caballero.