Biology subjects

Zuniga-Sanchez, E.

Publications and source records attributed to Zuniga-Sanchez, E..

3 recordsLinked to original sources

bioRxiv2026

Protocadherin 9 promotes cell survival of different bipolar subtypes in the developing mouse retina

Neural circuit assembly relies on different neuronal subtypes coming together to form a functional circuit. The question of how the appropriate number of each subtype 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 subtype integration in a developing circuit. In the mammalian retina, bipolar neurons are a class of interneurons that relay visual information from photoreceptors to ganglion cells. Extensive studies have shown there are 15 distinct bipolar subtypes: 6 types of OFF cone bipolars, 8 types of ON cone bipolars, and 1 type of rod bipolar. During retinal development, bipolar neurons are born in excess and through programmed cell death, a precise number of each subtype remains to give rise to the retinal circuit. Although this process has been well-described, little is known about the key molecules responsible for bipolar subtype integration in the developing retina. Our work uncovered a new role for the autism-associated risk gene, Protocadherin 9 (Pcdh9) in bipolar subtype integration. 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 bipolar subtype integration during retinal development. SUMMARY STATEMENTNeural circuits are comprised of multiple neuronal subtypes 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 subtype during circuit development. In the present study, we identified the autism risk gene, Protocadherin 9 as a critical molecule in subtype integration of bipolar neurons within the developing mouse retina. Using newly generated mouse lines, we found distinct requirements of Pcdh9 to promote survival in different bipolar subtypes during retinal circuit assembly. The significance of this work is that it shed lights into how different neuronal subtypes are integrated in nascent neural circuits.

neuroscience↗

bioRxiv2025

Ankyrins are essential for synaptic integrity of photoreceptors in the mouse outer retina

Retinal circuit assembly relies on the precise timing and positioning of key molecules between neuronal partners to mediate proper synapse formation. In the outer retina, horizontal cells are important interneurons that make the first contacts to photoreceptors and begin to segregate visual information into two distinct pathways by selectively forming synapses to the different types of photoreceptors. Dendrites of horizontal cells synapse exclusively to cone photoreceptors whereas the axon terminal synapses to rod photoreceptors. Failure to properly form these early connections disrupts the downstream connectivity of other postsynaptic neurons and leads to abnormal visual function. Although these early events are critical for proper synapse development, little is known about the molecular mechanisms that establish horizontal cell to photoreceptor connectivity during development. In the present study, we performed single-cell RNA sequencing and uncovered new molecules that are highly expressed in horizontal cells. These include different members of the cytoskeletal scaffolding family of Ankyrins that are known to form specialized regions within neurons by recruiting different molecules to the membrane and linking them to the cytoskeleton. Specifically, we found Ankyrin-B to be highly expressed in horizontal cells at early time points and Ankyrin-G to be expressed at later stages. Loss of both Ankyrin-B and Ankyrin-G leads to synaptic defects between horizontal cells and photoreceptors and disrupts in vivo retinal responses. In summary, our findings uncovered a new role for Ankyrins in mediating synaptic connectivity between horizontal cells and photoreceptors required for normal visual function. SIGNIFICANCE STATEMENTIn the mammalian retina, the first synapse between photoreceptors and their downstream targets begins to separate visual information into two distinct pathways. During retinal development, photoreceptors first make contacts to horizontal cells in a temporal- and spatial-specific manner. Although this initial contact is critical for synaptogenesis, little is known about the key molecules responsible for selective wiring of horizontal cells to photoreceptors. In this study, we performed single-cell RNA sequencing and identified the family of cytoskeletal scaffolding proteins Ankyrins to be differentially expressed in horizontal cells. Loss of Ankyrins impairs synaptic connectivity between horizontal cells and their photoreceptor partners leading to abnormal visual responses. Taken together, our work uncovered a new function of Ankyrins at photoreceptor synapses.

neuroscience↗

bioRxiv2022

bII-spectrin is required for synaptic positioning during retinal development

Neural circuit assembly is a multi-step process where synaptic partners are often born at distinct developmental stages, and yet they must find each other and form precise synaptic connections with one another. This developmental process often relies on late-born neurons extending their processes to the appropriate layer to find and make synaptic connections to their early-born targets. The molecular mechanism responsible for the integration of late-born neurons into an emerging neural circuit remains unclear. Here we uncovered a new role for the cytoskeletal protein {beta}II-spectrin in properly positioning pre- and post-synaptic neurons to the developing synaptic layer. Loss of {beta}II-spectrin disrupts retinal lamination, leads to synaptic connectivity defects, and results in impaired visual function. Together, these findings highlight a new function of {beta}II-spectrin in assembling neural circuits in the mouse outer retina. HighlightsO_LIEstablished a new role for {beta}II-spectrin in assembling retinal circuits C_LIO_LI{beta}II-spectrin positions pre- and post-synaptic neurons to the developing synaptic layer C_LIO_LIEarly positioning of processes to the OPL is required for synaptogenesis C_LIO_LILoss of {beta}II-spectrin disrupts synaptic connectivity and impairs visual function C_LI

neuroscience↗