Alternative splicing of a species- and skeletal muscle-specific microexon diversifies the menu of clathrin heavy chains in mice and rats.

Little is known about alternative splicing of microexons in most tissues other than the brain. Humans have two homologous clathrin heavy chains. Ubiquitously expressed, CLTC drives clathrin-mediated endocytosis. Highly expressed in skeletal muscles, CLTCL1 instead regulates glucose metabolism. Previously, we reported that a conserved microexon (exon 31) in the CLTC gene is alternatively spliced during striated muscle development. Here, we identified a novel Cltc microexon (exon 33, hereafter microexon 33), which is only included in mouse and rat adult skeletal muscles. Microexon 33 inclusion shortens the CLTC C-terminus and adds 10 distinct terminal residues. This divergence occurs at the same position at which the human CLTCL1 constitutively includes its penultimate exon (another microexon). CLTCL1 is a pseudogene in mice and rats. Humans diversified the menu of clathrin heavy chains by gene duplication and tissue-specific gene expression, whereas mice and rats might have achieved similar diversification by tissue-specific regulation of Cltc alternative splicing.