GlialCAM Cytoplasmic Signaling in Oligodendrocytes and Astrocytes is Essential for White Matter Homeostasis in the Brain

Glial cell adhesion molecule (GlialCAM) is an astrocyte- and oligodendrocyte-expressed transmembrane protein with two extracellular IgG-like domains and a cytoplasmic tail with putative signaling functions. While numerous studies have explored functions for the GlialCAM IgG-like domains in brain development and physiology, functions for its cytoplasmic signaling tail remain largely unknown. Therefore, we developed a mutant mouse model that expresses a truncated GlialCAM construct (GlialCAM ΔCT) that contains intact extracellular and transmembrane domains but lacks the cytoplasmic tail. Deletion of the GlialCAM cytoplasmic domain in glial cells of the brain results in vacuolization within white matter regions without disrupting neurovascular barrier integrity. Consequently, mutant mice exhibited selective deficits in motor coordination, muscular strength, and memory. Single cell transcriptome sequencing identifies GlialCAM-dependent defects in ECM remodeling pathways in white matter tracts. In situ spatial profiling revealed robust activation of astrocytes and microglia in the mutant brain. Proteomic analysis identified GlialCAM cytoplasmic tail interactors with links to MAPK signaling and cytoskeletal regulatory networks. These data reveal important functions for the GlialCAM cytoplasmic tail in homeostasis of white matter tracts in the adult murine brain. The GlialCAM ΔCT model may also be useful for studying the pathogenesis and possible treatment of neurological diseases linked to white matter degeneration.