The CAR group of Ig cell adhesion proteins–Regulators of gap junctions?

Abstract

Members of the CAR group of Ig-like type I transmembrane proteins mediate homotypic cell adhesion, share a common overall extracellular domain structure and are closely related at the amino acid sequence level. CAR proteins are often found at tight junctions and interact with intracellular scaffolding proteins, suggesting that they might modulate tight junction assembly or function. However, impairment of tight junction integrity has not been reported in mouse knockout models or zebrafish mutants of CAR members. In contrast, in the same knockout models deficits in gap junction communication were detected in several organ systems, including the atrioventricular node of the heart, smooth muscle cells of the intestine and the ureter and in Sertoli cells of the testes. Possible interactions between BT-IgSF and connexin41.8 on the disturbed pattern of pigment stripes found in zebrafish mutants and between ESAM and con-nexin43 during hematopoiesis in the mouse are also discussed. On the basis of the combined data and phenotypic similarities between CAR member mutants and connexin mutants I hypothesize that they primarily play a role in the organization of gap junction communication. Also see the video abstract here: https://youtu.be/i0yq2KhuDAE.

Immunoglobulin superfamily receptor Junctional adhesion molecule 3 (Jam3) requirement for melanophore survival and patterning during formation of zebrafish stripes

“…Our finding that homozygous jam3b; igsf11 mutants lacked nearly all melanophores suggests that Jam3b and Igsf11 have non-overlapping roles as well: perhaps Jam3b functions principally at adherens or tight junctions, whereas Igsf11 functions principally at gap junctions (Rathjen, 2020), which play essential roles in zebrafish adult pattern development (Irion et al, 2014; Usui et al, 2019; Watanabe et al, 2006; Watanabe et al, 2016). Interestingly, the melanophores that were found in double mutants were lightly melanized and limited to ventral regions of the flank, where some melanoblasts emerge during the larva-to-adult transition (Budi et al, 2011).…”

“…In jam3b mutants, behaviors of melanoblasts were similar to wild-type, suggesting that the requirement for Jam3b arises somewhat later than that for Igsf11 in this lineage. JAM and CAR receptors can interact with the same partners in other systems (Ebnet, 2017; Rathjen, 2020), and a genetic interaction— revealed as broken stripes in doubly heterozygous fish—suggests some functional overlap in zebrafish melanophores. Indeed, melanophores mutant for either gene had more dendritic phenotypes.…”

“…For example, several genes, including leopard , encode gap junction or tight junction proteins that are expressed and required by pigment cells, and when activities of these genes are perturbed, spots form instead of stripes (Fadeev et al, 2015; Irion et al, 2014; Mahalwar et al, 2016; Usui et al, 2019; Watanabe et al, 2006; Watanabe et al, 2016). A different class of adhesion molecule is represented by Coxsackie- and Adenovirus Receptor (CAR) and Junctional Adhesion Molecule (JAM) family genes, which encode dimeric cell surface adhesion receptors having extracellular regions with two immunoglobulin (Ig)-like domains and intracellular regions that interact with PDZ-containing proteins that function in scaffolding and signaling (Ebnet, 2017; Ebnet et al, 2004; Kummer and Ebnet, 2018; Rathjen, 2020; Schreiber et al, 2014). CAR and JAM family members participate in homophilic and heterophilic interactions in cis and trans to regulate cell-cell contacts, junctional adhesion, migration, motility, proliferation and polarity across a wide range of cell types.…”

Do CAR and CAR family members aid in gap junction formation?

“…may aid in connexon docking. [1] CAR stands for Coxsackie and Adenovirus Receptor, transmembrane proteins of the Ig-like cell adhesion protein superfamily that provide cell-cell adhesion via homophilic binding. They received their name as coxsackie, and adenoviruses use the protein as a receptor and to somehow move directly from cell to cell.…”

“…In article 2000031 of this issue, Fritz Rathjen presents novel and exciting evidence suggesting that CAR and CAR‐family members (BT‐IgSF, CLMP, ESAM) regulate gap junction function and indeed may aid in connexon docking. [ 1 ] CAR stands for Coxsackie and Adenovirus Receptor, transmembrane proteins of the Ig‐like cell adhesion protein superfamily that provide cell‐cell adhesion via homophilic binding. They received their name as coxsackie, and adenoviruses use the protein as a receptor and to somehow move directly from cell to cell.…”