Axin Family of Scaffolding Proteins in Development: Lessons from C. elegans

Abstract

Scaffold proteins serve important roles in cellular signaling by integrating inputs from multiple signaling molecules to regulate downstream effectors that, in turn, carry out specific biological functions. One such protein, Axin, represents a major evolutionarily conserved scaffold protein in metazoans that participates in the WNT pathway and other pathways to regulate diverse cellular processes. This review summarizes the vast amount of literature on the regulation and functions of the Axin family of genes in eukaryotes, with a specific focus on Caenorhabditis elegans development. By combining early studies with recent findings, the review is aimed to serve as an updated reference for the roles of Axin in C. elegans and other model systems.

Axin-mediated regulation of lifespan and muscle health inC. elegansinvolves AMPK-FOXO signaling

“…The involvement of PRY-1 in multiple signaling pathways and biological events is well documented (Mallick et al, 2019a). Earlier, we reported both mRNA and microRNA (miRNA) transcriptome profiles of pry-1 mutant that revealed 2,665 differentially expressed (DE) proteincoding genes and six miRNAs (Mallick et al, 2019b;Ranawade et al, 2018).…”

“…A similar phenotype is also observed in a CRISPR allele, gk3682, that deletes roughly 750 bp region including the 5' UTR and first exon (Mallick et al, 2019b) ( Figure 1C; Table S2). As pry-1 is also involved in developmental processes (Mallick et al, 2019a), we took an RNAi approach to knock down the gene function specifically during adulthood. As expected, pry-1(RNAi) animals were found to be short-lived, with a 22-31% reduction in the mean lifespan ( Figure 1D; Table S2).…”

“…The involvement of Axin in AMPK complex formation is essential since Axin knockdown drastically reduces AMPK activity, leading to fatty liver in starved mice (Zhang et al, 2013b). In addition to their role in AMPK regulation, Axin family members are also involved in multiple biological processes during development and post-development (Mallick et al, 2019a). Since its discovery as a negative regulator of WNT signaling, Axin is demonstrated to participate in other, non-WNT, pathways as well.…”

“…Since its discovery as a negative regulator of WNT signaling, Axin is demonstrated to participate in other, non-WNT, pathways as well. In all cases, a common thread is Axin's role as a scaffold protein to recruit other factors to form complexes (Mallick et al, 2019a). However, whether the scaffolding role of Axin affects FOXO activity remains to be investigated.…”

Significant Associations between AXIN1 rs1805105, rs12921862, rs370681 Haplotypes and Variant Genotypes of AXIN2 rs2240308 with Risk of Congenital Heart Defects

“…Variants of AXIN1 and AXIN2 genes, or of the other components of the signaling pathway, may influence the gene activity and also β-catenin mRNA levels [ 7 ], therefore, being involved in the development and/or progression of diseases such as cryptorchidism [ 8 ], congenital septal heart defects [ 9 ], hepatocellular carcinoma [ 10 ], colorectal carcinoma [ 11 ], and lung and other types of cancers [ 12 ]. Previous experimental studies demonstrated that AXIN1 and AXIN2 had a crucial role in cell proliferation and heart development [ 13 ]. Also, experimental studies such as the study performed by Lei Ji et al [ 14 ] confirmed that several variants of AXIN1 and AXIN2 genes were pathogenic variants associated with heart abnormalities [ 14 ].…”