*2.2. Neighboring Cells*

Müller glia are radial cells that span much of the neurosensory retina, reaching from the internal limiting membrane at the vitreal surface of the retina to the external limiting membrane on the scleral edge of the ONL [25]. Within the ONL, fine Müller cell extensions appear to ensheath the PR cell soma. As they also interact with vascular layers within the retina, Müller cells may provide essential nutrients to PR cells, which do not directly contact the circulation. They also regulate extracellular volume, ion and water homeostasis, serve to modify neuronal activity through release of neuroactive compounds, and modulate immune and inflammatory responses [26]. At the external limiting membrane, Müller cell endfeet engage rod and cone cell ISs in intercellular adhesion interactions, including tight junctions, which create a di ffusion barrier. Notably, the arrangemen<sup>t</sup> of an Müller cell, rods, and a cone cell has been proposed to form a columnar unit (Figure 1b), which may result in physiological and functional coordination of these cell types.

RPE cells (Figure 1b,c) constitute an epithelial monolayer that lies between the retina and a capillary bed, the choriocapillaris. The flow of water, ions, small molecules, and metabolites from the blood to the outer retina is thus regulated by RPE cells. Their apical surface features microvilli and microplicae (Figure 1b,c) that contact roughly the outermost third of OSs and play important roles in recycling molecules needed for PR renewal. These apical processes also mediate initial steps in the daily phagocytosis of OS tips. As an epithelium with high-resistance intercellular junctions [27], the RPE performs an important barrier function, disruption of which may cause PR degeneration.

Microglial cells form ramified networks within the same retinal layers as the retinal vasculature, which includes the superficial, intermediate and deep vascular beds. Microglia at the level of the outer plexiform layer in healthy retinas extend dendritic arms into the ONL (Figure 1b), where they contact PR soma as part of a dynamic survey process. During development and in rare events that occur in healthy retinas, these cells engulf and phagocytose PR soma, presumably in response to a defect in PR function.

PRs form synaptic connections in the outer plexiform layer with secondary neurons, including bipolar and horizontal cells. Although these connections are critical for signal transmission, they are not as extensive as the contacts made between PRs and Müller glia, RPE cell apical processes, or the dynamic extensions on microglial cells, and were therefore omitted from the summary diagram in Figure 1. Nevertheless, perturbation of the interactions among these cells may lead to PR degeneration, conceivably due to an alteration of signal transmission.

### *2.3. Inherited Diseases that Cause PR Cell Loss*

Major monogenic inherited RDs in which PR cells are lost include: retinitis pigmentosa [28], Leber congenital amaurosis [29], and syndromic disorders that manifest disease in multiple organs, including the eye, particularly ciliopathies, such as Joubert [30], Bardet–Biedl [31], or Usher [32] syndrome. The remarkable success of gene augmentation therapy for a form of Leber congenital amaurosis has invigorated research e fforts to treat these diseases [33].
