Novel Kidins220/ARMS Splice Isoforms: Potential Specific Regulators of Neuronal and Cardiovascular Development

Abstract

Kidins220/ARMS is a transmembrane protein playing a crucial role in neuronal and cardiovascular development. Kidins220/ARMS is a downstream target of neurotrophin receptors and interacts with several signalling and trafficking factors. Through computational modelling, we found two potential sites for alternative splicing of Kidins220/ARMS. The first is located between exon 24 and exon 29, while the second site replaces exon 32 by a short alternative terminal exon 33. Here we describe the conserved occurrence of several Kidins220/ARMS splice isoforms at RNA and protein levels. Kidins220/ARMS splice isoforms display spatio-temporal regulation during development with distinct patterns in different neuronal populations. Neurotrophin receptor stimulation in cortical and hippocampal neurons and neuroendocrine cells induces specific Kidins220/ARMS splice isoforms and alters the appearance kinetics of the full-length transcript. Remarkably, alternative terminal exon splicing generates Kidins220/ARMS variants with distinct cellular localisation: Kidins220/ARMS containing exon 32 is targeted to the plasma membrane and neurite tips, whereas Kidins220/ARMS without exon 33 mainly clusters the full-length protein in a perinuclear intracellular compartment in PC12 cells and primary neurons, leading to a change in neurotrophin receptor expression. Overall, this study demonstrates the existence of novel Kidins220/ARMS splice isoforms with unique properties, revealing additional complexity in the functional regulation of neurotrophin receptors, and potentially other signalling pathways involved in neuronal and cardiovascular development.

Functions of the multi‐interacting protein KIDINS220/ARMS in cancer and other pathologies

“…SINO syndrome is characterized by spastic paraplegia, intellectual disability, nystagmus and obesity. The variants of KIDINS220 responsible for this sort of syndrome were closely related to an isoform of KIDINS220 with alternative splicing and present only in adult tissues . The study has shown the importance of the delicate balance of KIDINS220 isoforms' expression during the developmental phases of an embryo .…”

“…The variants of KIDINS220 responsible for this sort of syndrome were closely related to an isoform of KIDINS220 with alternative splicing and present only in adult tissues. 46 The study has shown the importance of the delicate balance of KIDINS220 isoforms' expression during the developmental phases of an embryo. 45 Other genetic variants were found in unborn fetuses corresponding to a premature termination codon in exon 25 resulting in nonsense-mediated mRNA decay and absence of protein.…”

Differential regulation of Kidins220 isoforms in Huntington's disease

“…Kidins220 is an integral membrane protein essential for neurotrophin signaling that interacts both with Trks and p75 NTR . Recent studies have revealed that Kidins220 shows alternative splicing variants determining the presence or the absence of critical protein–protein interaction domains, which may cause still unexplored structural and functional changes . Specifically, in mouse and human adult brain, Kidins220 presents two main isoforms as the result of alternative terminal exon splicing from exon 31 to exon 32 or to exon 33 .…”

“…Recent studies have revealed that Kidins220 shows alternative splicing variants determining the presence or the absence of critical protein–protein interaction domains, which may cause still unexplored structural and functional changes . Specifically, in mouse and human adult brain, Kidins220 presents two main isoforms as the result of alternative terminal exon splicing from exon 31 to exon 32 or to exon 33 . These variants, known as full length and C2 and here respectively named Kidins220‐C32 and Kidins220‐C33, strongly differ in their carboxy‐terminal (C‐terminal) length and sequences .…”

“…Specifically, in mouse and human adult brain, Kidins220 presents two main isoforms as the result of alternative terminal exon splicing from exon 31 to exon 32 or to exon 33 . These variants, known as full length and C2 and here respectively named Kidins220‐C32 and Kidins220‐C33, strongly differ in their carboxy‐terminal (C‐terminal) length and sequences . In this regard, Kidins220‐C33 isoform lacks the kinesin‐interacting motif (KIM), the p75 NTR binding site and the PDZ‐ligand, all domains encoded by exon 32.…”