Protocadherin 9 Promotes Cell Survival of Different Bipolar Cell Types in the Developing Mouse Retina

Abstract

Neural circuit assembly relies on different neuronal types coming together to form a functional circuit. The question of how the appropriate number of each type is integrated into an emerging circuit remains relatively unknown. To answer this question, we used the mouse retina to uncover the molecular mechanisms responsible for neuron-type integration in a developing circuit. In the mammalian retina, bipolar cells (BCs) are a class of interneurons that relay visual information from photoreceptors to ganglion cells. Extensive studies have shown there are 15 distinct BC types: 6 types of OFF cone bipolars, 8 types of ON cone bipolars, and 1 type of rod bipolar. During retinal development, BCs are born in excess, and through programmed cell death, a precise number of each type remains to give rise to the retinal circuit. Although this process has been well described, little is known about the key molecules responsible for BC-type integration in the developing retina. Our work uncovered the new role of the autism-associated risk gene, Protocadherin 9 ( Pcdh9 ), in BCs of both male and female mice. Deletion of Pcdh9 using a floxed allele leads to loss of OFF and ON cone bipolars; however, disruption in the extracellular binding of Pcdh9 leads to selective loss of ON cone bipolars but not rod bipolars. Moreover, we found this later function of Pcdh9 is mediated by homophilic interactions between ON cone bipolars and their known synaptic partners. Taken together, our work revealed the new role of Pcdh9 in retinal development.