Astrocytes express aberrant immunoglobulins as putative gatekeeper of astrocytes to neuronal progenitor conversion

Abstract

Using multi-omics analyses including RNAseq, RT-PCR, RACE-PCR, and shotgun proteomic with enrichment strategies, we demonstrated that newborn rat astrocytes produce neural immunoglobulin constant and variable heavy chains as well as light chains. However, their edification is different from the ones found in B cells and they resemble aberrant immunoglobulins observed in several cancers. Moreover, the complete enzymatic V(D)J recombination complex has also been identified in astrocytes. In addition, the constant heavy chain is also present in adult rat astrocytes, whereas in primary astrocytes from human fetus we identified constant and variable kappa chains as well as the substitution lambda chains known to be involved in pre-B cells. To gather insights into the function of these neural IgGs, CRISPR-Cas9 of IgG2B constant heavy chain encoding gene (Igh6), IgG2B overexpression, proximal labeling of rat astrocytes IgG2B and targets identification through 2D gels were performed. In Igh6 KO astrocytes, overrepresentation of factors involved in hematopoietic cells, neural stem cells, and the regulation of neuritogenesis have been identified. Moreover, overexpression of IgG2B in astrocytes induces the CRTC1-CREB-BDNF signaling pathway known to be involved in gliogenesis, whereas Igh6 KO triggers the BMP/YAP1/TEAD3 pathway activated in astrocytes dedifferentiation into neural progenitors. Proximal labeling experiments revealed that IgG2B is N-glycosylated by the OST complex, addressed to vesicle membranes containing the ATPase complex, and behaves partially like CD98hc through its association with LAT1. These experiments also suggest that proximal IgG2B-LAT1 interaction occurs concomitantly with MACO-1 and C2CD2L, at the heart of a potentially novel cell signaling platform. Finally, we demonstrated that these chains are synthesized individually and associated to recognize specific targets. Indeed, intermediate filaments Eif4a2 and Pdia6 involved in astrocyte fate constitute targets for these neural IgGs. Taken together, we hypothese that neural aberrant IgG chains may act as gatekeepers of astrocytes' fate.

A Unifying Hypothesis for the Genome Dynamics Proposed to Underlie Neuropsychiatric Phenotypes

“…Antibody production was also demonstrated in astrocytes which are increasingly linked with neurobehavioral changes and where astrocytes were found to exhibit the classic enzymatic machinery involved in V(D)J recombination [79]. Furthermore, gene conversion involving pseudogenic sequences during class switch conversion or recombination of the constant region increases the creation of a vast diversity of immunological recognition molecules from a limited number of initial gene segments [81].…”

A Unifying Hypothesis for the Genome Dynamics Proposed to Underly Neuropsychiatric Phenotypes

“…A component of the immune system recombinase (RAG-1) is expressed in cortical and hippocampal NPCs during mouse neurodevelopment. Antibody production was also demonstrated in astrocytes which are increasingly linked with neurobehavioral changes and where astrocytes were found to exhibit the classic enzymatic machinery involved in V(D)J recombination [82]. Furthermore, gene conversion involving pseudogenic sequences during class switch conversion or recombination of the constant region increases the creation of a vast diversity of immunological recognition molecules from a limited number of initial gene segments [83].…”