2026/07/16 by Marlon F Mattos, Daniela Becerril, Jingyao Guo +3 · 1 voice
Biochemistry, Genetics and Molecular Biology · #Developmental Biology and Gene Regulation #Retinal Development and Disorders #Wnt/β-catenin signaling in development and cancer
paper · doi:10.1523/jneurosci.0184-26.2026
openalex publication_date 2026/07/16 · openalex created_date 2026/07/17 · openalex updated_date 2026/07/18
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 (BC) 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 a new role for 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 a new role for Pcdh9 in retinal development. Significance statement Neural circuits are comprised of multiple neuronal types where a specific number need to come together to give rise to a functional circuit. Although this is a critical process during neurodevelopment, little is known about the molecular mechanisms that determines the precise number of each type during circuit development. In the present study, we identified the autism risk gene, Protocadherin 9 as a critical molecule in neuronal type integration of bipolar cells within the developing mouse retina. Using newly generated mouse lines, we found distinct requirements of Pcdh9 to promote survival in different BCs during retinal circuit assembly. The significance of this work is that it shed lights into how different neuronal types are integrated in nascent neural circuits.