Complete congenital achromatopsia is a devastating hereditary visual disorder, which is associated with a deficient cone-mediated electroretinogram (ERG) response, color blindness, visual acuity loss, pendular nystagmus, extreme light sensitivity and daytime blindness (1– 3).
Furthermore, the authors suggested that RB1-deficient cone precursors form differentiated retinoblastomas that subsequently dedifferentiate and acquire non-cone characteristics, in line with our observations.
In RPE65-deficient patients, cone loss is observed in both the fovea [34] and the periphery, which is mainly populated by S-cones and first affected [35], [36].
To assess the potential aberrations in the intracellular staining of growth-cone related proteins, we also immunostained neuronal cultures from Cln1 and Cln5 deficient mice for the growth cone assembly protein GAP-43 and synapsin, two well known markers for growth cone integrity, together with Rab3 which was differentially expressed according to our transcript profiling data.
In addition, the enhanced integration observed in the cone-deficient retinae may be beneficial for cell-transplantation therapies.
Moreover, transplantation of embryonic-stage Crx-expressing donor cells into a cone-deficient retina, the Gucy2e −/− model of LCA, resulted in a higher proportion of cones among the total number of integrated photoreceptor cells.
Remarkably, CadN-deficient R7 growth cones retain the ability to jump between distal medulla layers for days after their normal targeting should have been concluded and stabilized, presumably through the filopodial dynamics described here.
Genetic or pharmacological inactivation of p110δ in sensory neurons led to a reduction in PI3K signaling, increased sensitivity to growth cone collapse and deficient axonal elongation under limiting growth conditions.
GAP-43 is critically involved in nerve regrowth because depletion of GAP-43 in neuronal growth cones leads to deficient spreading and branching of nerve fibres [ 42], whereas overexpression of GAP-43 induces spontaneous nerve sprouting and a highly potentiated sprouting response with branching after nerve lesions in transgenic mice [ 43].
Without a functional RPE65 gene, rod and cone photoreceptor cells become deficient in 11-cis retinal and are unable to respond to light [1].
From this point of view, Rpe65-deficient mice are interesting models to study cone degeneration, since in this case cone loss occurs before rod loss [6].
