Strip1 regulates retinal ganglion cell survival by suppressing Jun-mediated apoptosis to promote retinal neural circuit formation

Abstract

In the vertebrate retina, an interplay between retinal ganglion cells (RGCs), amacrine (AC), and bipolar (BP) cells establishes a synaptic layer called the inner plexiform layer (IPL). This circuit conveys signals from photoreceptors to visual centers in the brain. However, the molecular mechanisms involved in its development remain poorly understood. Striatin-interacting protein 1 (Strip1) is a core component of the striatin-interacting phosphatases and kinases (STRIPAK) complex, and it has shown emerging roles in embryonic morphogenesis. Here, we uncover the importance of Strip1 in inner retina development. Using zebrafish, we show that loss of Strip1 causes defects in IPL formation. In strip1 mutants, RGCs undergo dramatic cell death shortly after birth. AC and BP cells subsequently invade the degenerating RGC layer, leading to a disorganized IPL. Mechanistically, zebrafish Strip1 interacts with its STRIPAK partner, Striatin 3 (Strn3), and both show overlapping functions in RGC survival. Furthermore, loss of Strip1 or Strn3 leads to activation of the proapoptotic marker, Jun, within RGCs, and Jun knockdown rescues RGC survival in strip1 mutants. In addition to its function in RGC maintenance, Strip1 is required for RGC dendritic patterning, which likely contributes to proper IPL formation. Taken together, we propose that a series of Strip1-mediated regulatory events coordinates inner retinal circuit formation by maintaining RGCs during development, which ensures proper positioning and neurite patterning of inner retinal neurons.

scQA: A dual-perspective cell type identification model for single cell transcriptome data

“…Another gene, Strip2 , also exhibits strong specificity in expression with a percentage of 90.7% of expressed cells being RBCs which is not documented in any reference as a marker gene. Strip2 may be relevant to retinal development since a recent study highlighted the importance of Strip1 in inner retina development [65] and both Strip1 and Strip2 play a role in regulating cell morphology and cytoskeletal organization and are paralogs to each other. The analysis indicates that scQA possesses the capability to create a landmark for similar marker genes identified, and facilitates the detection of new marker genes.…”

Clustering scRNA-seq data via qualitative and quantitative analysis

“…Another gene, STRIP2 , also exhibits strong specificity in expression with a percentage of 90.7% of expressed cells being RBCs which we have not found in any reference recorded as a marker gene. STRIP2 may be relevant to retinal development since a recent study highlighted the importance of STRIP1 in inner retina development (Ahmed et al 2022) and both STRIP1 and STRIP2 play a role in regulating cell morphology and cytoskeletal organization and are paralogs to each other. Thus, scQA has the potential to detect new marker genes.…”

Circuit mechanisms underlying embryonic retinal waves

“…Thus, stage 1 and 2 retinal waves are not required for ipRGC apoptosis; however, it is possible that the residual wave activity in β2-nAChR-KO is sufficient to activate pro-survival pathways. A deeper understanding of how spontaneous activity modulates RGC survival pathways (e.g., Ahmed et al, 2022 ) is warranted.…”