ASF/SF2 and SC35 regulate the glutamate receptor subunit 2 alternative flip/flop splicing

Abstract

The properties of the glutamate receptor subunits 1-4 (GluR1-4) are influenced by the alternative splicing of two homologous and mutually exclusive exons flip and flop. The flip form is most abundant during early development, while the flop form is dominant in adults. From transfections with a GluR2 mini-gene we show that flip is the preferred splice form in all tested cell lines, but coexpression of the SR-proteins ASF/SF2 and SC35 increases the flop to flip splice ratio. The increased flop incorporation depends on ASF/SF2-and SC35-dependent enhancer elements located in the flop exon, which stimulate the splicing between the flop exon and the preceding exon 13.

Alternative splicing factor or splicing factor‐2 plays a key role in intron retention of the endoglin gene during endothelial senescence

“…2). These results are compatible with the antagonistic role widely described for both SR protein family members on the regulation of alternative splicing in different genes (Tacke & Manley, 1995), such as the growth hormone gene (Solis et al, 2008) and the glutamate receptor subunit 2 gene (GluR2) (Crovato & Egebjerg, 2005). Trans-elements, or splicing factors, act by means of binding to short degenerate sequences of low complexity, and these protein ⁄ RNA interactions can be studied by RNA immunoprecipitation (RIP) (Zielinski et al, 2006).…”

Distribution of SRPK1 in human brain

“…SRPK1 is accomplishing its function through the phosphorylation of the ubiquitously expressed SR splicing factors that are involved in the regulation of pre-mRNA splicing and other steps of RNA metabolism. Interestingly, the distribution of SRp38 -that is known to regulate alternative splicing of GluR2 (Crovato and Egebjerg, 2005;Feng et al, 2008) -in CNS seems to be quite similar to that described here for SRPK1 (Liu et al, 2003). Phosphorylation of SR proteins is critical in mediating the assembly of highly specific spliceosomal complexes together with neuronal regulators of alternative splicing such as Tra2b, the neuronal polypyrimidine tract-binding protein (nPTB), embryonic lethal-abnormal vision (ELAV), Feminizing gene on X (FOX), and neuron-oncological ventral proteins (Nova) (Loya et al, 2010, and references therein).…”

“…For example, ASF/SF2, SC35 and SRp38, which are all efficiently targeted by SRPK1 (Xiao and Manley, 1997;Shi and Manley, 2007), have been shown to regulate alternative splicing of glutamate receptor subunit 2 (GluR2) in the nervous system. Co-expression of ASF/SF2 and SC35 in neurons increases the flop to flip splice ratio of GluR2 (Crovato and Egebjerg, 2005), while phosphorylated SRp38 promotes the inclusion of flip exon in GluR2 pre-mRNA splicing (Feng et al, 2008). Furthermore, SRPK1, through the phosphorylation of a variety of SR proteins, has been previously reported to regulate the alternative splicing of tau protein and in particular exon 10 splicing, which has been involved in the pathogenesis mainly of Frontotemporal Dementia and to a lesser extent in other tauopathies, such as Alzheimer disease (Hartmann et al, 2001;Andreadis, 2011, and references therein).…”

Characterization of Tissue-Specific and Developmentally Regulated Alternative Splicing of Exon 64 in theCOL5A1Gene

“…The near identity of their DNA sequences indicates that they likely arose from a duplication event. Inclusion of “flip” occurs during development, while adult tissues use “flop” [15]. These exons are separated by a 413 bp intron, which is large enough to permit inclusion of both exons in a single message.…”