RTN4/NoGo-receptor binding to BAI adhesion-GPCRs regulates neuronal development

Abstract

In the introduction of the original article, we neglected to cite a previous systematic receptor-ligand interaction screen that identified, among others, binding of BAI1 TSR domains to RTN4Rs and lack of binding of BAI2 (Chong et al., 2018

Post-injury born oligodendrocytes integrate into the glial scar and inhibit growth of regenerating axons by premature myelination

“…Such myelin-associated inhibitors that are presented on the surface of oligodendrocytes include, NogoA 68 and Omgp 69 . BAIs also were recently discovered to inhibit axon growth by live oligodendrocytes co-cultured with neurons 27 . Thus, we investigated whether these inhibitors of axon growth are expressed by post-injury-born immature oligodendrocytes.…”

“…Thus, it is possible that primarily the premature de novo myelination, rather than the pre-existing myelin and its debris, is what stalls experimental regeneration even after axons have bypassed the inhibitory glial scar. Indeed, conditional deletion in oligodendrocytes of the neurological diseases-associated brain-specific angiogenesis inhibitors (BAIs; which bind to the axon growth-inhibitory NogoA reticulon-4 receptor; Rtn4R), was recently shown to rescue axonal growth of co-cultured neurons 27 , further supporting our hypothesis that live oligodendrocytes, and not only their debris after injury, could inhibit axon regeneration. To test our hypothesis, we used single cell RNA-seq (scRNA-seq) to analyze the effects of ONC on optic nerve oligodendrocytes, and a cuprizone-induced chronic demyelination (that injures oligodendrocytes to model multiple sclerosis) during traumatic optic neuropathy (modeled by ONC), which acutely and irreversibly disrupts the neuronal axons while modifying the extra-axonal tissue environment 2 .…”

“…Some of the prominent myelin-associated inhibitors of axon growth, NogoA 68 and Omgp 69 , are membrane proteins that can be presented by live immature oligodendrocytes to inhibit axon regeneration, without needing to be exposed to axonal receptors specifically on myelin debris only after oligodendrocyte's death. BAIs also were recently discovered to inhibit axon growth by live oligodendrocytes cocultured with neurons 27 . Indeed, we found that NogoA, Omgp, and BAI1-2 are moderately expressed in oligodendrocytes newly-born after optic nerve injury, through which they could inhibit axon regeneration.…”

O-fucosylation stabilizes the TSR3 motif in thrombospondin-1 by interacting with nearby amino acids and protecting a disulfide bond

“…Recent data suggests that O -fucosylation on TSRs is not only important for folding and secretion but has functions in the extracellular environment as well. A recent study showed that an O -fucose on TSR3 of brain-specific angiogenesis inhibitor 1 (BAI1) is in direct contact with its ligand, reticulon-4 receptor (RTN4R) ( 42 ). BAI–RTN4R interactions control dendritic arborization, axon elongation, and synapse formation.…”

Isoform- and ligand-specific modulation of the adhesion GPCR ADGRL3/Latrophilin3 by a synthetic binder

“…With 33 members in the human genome, adhesion G protein-coupled receptors (aGPCRs) represent the second-largest subfamily of GPCRs. Genetic studies have identified critical roles for aGPCRs in development, immunity, and neurobiology 1 – 7 linking them to numerous diseases including neurodevelopmental disorders, deafness, male infertility, schizophrenia, immune disorders, and cancers 2 , 8 – 15 . While aGPCRs are crucial surface receptors involved in numerous physiological processes 16 , establishing an understanding of their mechanisms of action at the molecular level remains an ongoing challenge, as has been the development of tools to more effectively study them and to modulate their functions.…”