CUG-BP, Elav-like family (CELF)-mediated alternative splicing regulation in the brain during health and disease

Abstract

Alternative splicing is an important mechanism for generating transcript and protein diversity. In the brain, alternative splicing is particularly prevalent, and alternative splicing factors are highly enriched. These include the six members of the CUG-BP, Elav-like family (CELF). This review summarizes what is known about the expression of different CELF proteins in the nervous system and the evidence that they are important in neural development and function. The involvement of CELF proteins in the pathogenesis of a number of neurodegenerative disorders, including myotonic dystrophy, spinocerebellar ataxia, fragile X syndrome, spinal muscular atrophy, and spinal and bulbar muscular atrophy is discussed. Finally, the known targets of CELF-mediated alternative splicing regulation in the nervous system and the functional consequences of these splicing events are reviewed. This article is part of a Special Issue entitled "RNA and splicing regulation in neurodegeneration."

Keywords: APP; Alternative splicing; Amyloid precursor protein; Brain; CELF; CLIP; CUG-BP, Elav-like family; Crosslinking immunoprecipitation; DM1; GABT4; Gamma-aminobutyric acid transporter 4; MAPT; MBNL; Microtubule-associated protein tau; Muscle blind-like; Myotonic dystrophy; Myotonic dystrophy type 1; N-methyl-d-aspartate receptor 1; NF1; NMDAR1; Neurofibromin 1; Neurological disorders; Neurons; SBMA; SCA; SMA; SMN; Spinal and bulbar muscular atrophy; Spinal muscular atrophy; Spinocerebellar ataxia; Survival motor neuron.

Figure 1. Known targets of CELF-mediated alternative splicing regulation in the brain

A) Skipping of gamma-aminobutyric acid transporter 4 (Gabt4) exon 7 leads to the inclusion of a premature termination codon. Over-expression of CELF1 in a neuroblastoma cell line induced inclusion of exon 7 in endogenous transcripts. B) CELF2 and CELF4 promote N-methyl-D-aspartate receptor 1 (NMDAR1) exon 5 skipping, whereas CELF2 induces exon 21 inclusion. C) Microtubule-associated protein tau (MAPT) exon 2/3 skipping is induced by over-expression of CELF2. CELF4 has been shown be an inhibitor or mild activator of exon 2 inclusion, depending on the cell type used in the experiment; activation of exon 2 inclusion was demonstrated using a minigene lacking exon 3. MAPT exon 6 has three alternative 3’ splice sites. CELF5 and CELF6 mildly increase complete inclusion (6c) or skipping of exon 6 altogether at the expense of the 6p variant. CELF3 and CELF4 have been shown to strongly induce MAPT exon 10 inclusion. D) CELF1 promotes amyloid beta precursor protein (APP) exon 8 skipping. Regulation by CELF1 was tested in the absence of exon 7, which is also alternatively spliced. E) Over-expression of CELF1-5 proteins in non-neuronal cells promotes skipping of Neurofibromin 1 (NF1) exon 23a, whereas repression of CELF activity promotes exon 23a inclusion. Exons and introns are not drawn to scale.