Ancient origin of the rod bipolar cell pathway in the vertebrate retina

Abstract

Vertebrates rely on rod photoreceptors for vision in low-light conditions1. Mammals have a specialized downstream circuit for rod signaling called the primary rod pathway, which comprises specific cell types and wiring patterns that are thought to be unique to this lineage2–6. Thus, it has been long assumed that the primary rod pathway evolved in mammals3, 5–7. Here, we challenge this view by demonstrating that the mammalian primary rod pathway is conserved in zebrafish, which diverged from extant mammals ∼400 million years ago. Using single-cell RNA-sequencing, we identified two bipolar cell (BC) types in zebrafish that are related to mammalian rod BCs (RBCs) of the primary rod pathway. By combining electrophysiology, histology, and ultrastructural reconstruction of the zebrafish RBCs, we found that, like mammalian RBCs8, both zebrafish RBC types connect with all rods and red-cones in their dendritic territory, and provide output largely onto amacrine cells. The wiring pattern of the amacrine cells post-synaptic to one RBC type is strikingly similar to that of mammalian RBCs, suggesting that the cell types and circuit design of the primary rod pathway have emerged before the divergence of teleost fish and amniotes (mammals, birds, reptiles). The second RBC type in zebrafish, which forms separate pathways from the first RBC type, is either lost in mammals or emerged in fish to serve yet unknown roles.Highlights-Zebrafish have two rod bipolar cell types (RBC1/2).-Synaptic connectivity of RBC1 resembles that of the mammalian RBCs.-The primary rod pathway therefore probably evolved more than 400 million years ago.-The second zebrafish RBC type, RBC2, forms a separate pathway from RBC1.

Molecular Characterization of the Sea Lamprey Retina Illuminates the Evolutionary Origin of Retinal Cell Types

“…Interestingly, transcriptomic mapping results suggested the presence of two ON-type RBC types in the lamprey, mirroring recent findings of two ON RBC types in zebrafish (Fig. 3f, 3g) 48 . Last, a critical component of the mammalian rod pathway, the AII-AC, is closely aligned to lamprey AC8 (Fig.…”

“…4b). We suspect that both of these cells are ON rod BCs and may be related to the two types of ON rod BCs recently characterized in zebrafish retina 48 . Unlike mammals, lamprey have a rod bipolar cell that is hyperpolarizing, which could be BC7 49 .…”

“…The AII ACs then form gap junctions and inhibitory synapses with ON and OFF CBCs, which in turn connect to RGCs 80,81 . This indirect mechanism of rod signaling was once thought to be exclusive to mammals, but recent molecular and connectivity characterizations of the rod pathway in zebrafish have indicated that at least some lower vertebrates may also process rod signals in this fashion 48 .…”