Genetic interrogation reveals mechanisms regulating nexus glia development and shaping heart physiology

Functional organs require precise cellular organization to engage in bidirectional communication with the nervous system. However, the cellular specialization underlying this vital communication remains incompletely understood. Here, we investigated zebrafish cardiac nexus glia and found that they are post-mitotic and exhibit dynamic Ca²⁺ transients that mature throughout development and coordinate with cardiomyocyte activity. We demonstrate that mechanical cues are dispensable for nexus glia abundance. Using a large-scale CRISPR screen of genes identified from single-cell RNA sequencing (scRNA-seq) analysis of embryonic human cardiac cells, we identify nexus glia genetic modifiers. Specifically, perturbation of cdh6 expands the nexus glia population, enhances glial calcium activity, and disrupts cardiomyocyte calcium handling. Crucially, this glial overexpansion protects against cardiac exhaustion via a potassium channel-dependent mechanism. These findings reveal the genetic architecture of neuro-cardiac communication and highlight the role of nexus glia in cardiac resilience.