Figure 2. Losing vision - pathogenic convergence.

(A) Gene regulatory networks control the differentiation of retinal precursor cells into rod and cone photoreceptors. These networks also help maintain cell fate and survival.

(B) The connecting cilium links outer segments (specialized sensory cilia) to the inner segment by the connecting cilium, where it is anchored via the basal bodies. The axoneme forms the microtubule backbone of the connecting cilium.

(C) Phototransduction cascade converts photon absorption by the photopigment (i.e., opsin plus chromophore) into an electrical signal by controlling cyclic nucleotide-gated channels in the outer segment plasma membrane.

(D) After photoisomerization from 11-cis-retinal (11cRAL) to all-trans-retinal (atRAL), the chromophore is recycled in a multi-step process involving enzymes in different color-coded cell types. Whereas rods rely entirely on the visual cycle through the RPE, cones can utilize 11-cis-retinol (11cROL) produced by an alternative visual cycle through the Müller glia.

(E) Proteins are synthesized and folded in the endoplasmic reticulum (ER). Misfolded proteins in the ER trigger stress responses (unfolded protein response and heat shock response). Misfolded proteins and toxic aggregates can be cleared by the ubiquitin-proteasome system (UPS) and degraded by the lysosomes (including via autophagy).

(F) Complex pre- and postsynaptic machinery and transsynaptic complexes regulate signal transmission from photoreceptors to bipolar cells. The molecular mechanisms of this process are best understood at the synapse between photoreceptors and ON bipolar cells (including rod bipolar cells) illustrated here.