CELSR2 AND WNT5B COOPERATE IN SHAPING RETINAL HORIZONTAL CELL NEURITES

The seven-pass transmembrane cadherin Celsr2 is a core member of the Planar cell polarity (PCP) signaling pathway. Studies show that Celsr2 regulates several processes in neural development, including neuron migration, cilia development, and synapse formation, but its role in retinal development remains elusive. Wnts may be the upstream signal of PCP, and Wnt5b is expressed in the retina; however, its role in retinal development remains unclear. Here, we studied the role of Celsr2 and Wnt5b in retinal development. Celsr2 was expressed in retinal horizontal cells, ganglion cells, and Müller cells. We investigated the role of Celsr2 in the development of mouse retinal horizontal cells. Abnormal neurites sprouting from horizontal cells were observed in Celsr2 knockout mice. Retinal function was decreased in Celsr2 knockout mice based on ERG recording. Ectopic synaptic connections were detected in knockout mice using PSD95 staining. The expression of synaptic-associated proteins such as Bassoon and Cacna1s was downregulated. Wnt5b was expressed in retinal bipolar cells and ganglion cells. The phenotypes of Wnt5b knockout mice were similar to those of Celsr2 knockout mice. To find the genetic interaction between PCP members and Wnts, we generated several double heterozygous mice. Abnormal retinal horizontal cell sprouting was observed in the double heterozygote of Wnt5b and Celsr2, suggesting Wnt5b may be upstream of Celsr2. Moreover, horizontal cell sprouting was highly evident in double-knockout mice. These results suggest that Celsr2 and Wnt5b interact genetically, coregulate neurite outgrowth in retinal horizontal cells, and modulate synaptic connections in the retinal OPL.