Mus musculus
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REPOSITORIES: ENA
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Project description:Neuronal alternative splicing is dynamically regulated in a spatiotemporal fashion. We previously found that STAR family proteins (SAM68, SLM1, SLM2) regulate spatiotemporal alternative splicing in the nervous system. However, the whole aspect of alternative splicing programs governed by STARs remains unclear. We deciphered the alternative splicing programs of SAM68 and SLM1 proteins using transcriptomics. We reveal that SAM68 and SLM1 encode distinct alternative splicing programs; SAM68 preferentially controls alternative last exon (ALE) splicing. Interleukin 1-receptor accessory protein (Il1rap) is a novel target for SAM68. The usage of Il1rap ALEs results in mainly two variants encoding two functionally different isoforms, a membrane-bound (mIL1RAcP) and a soluble (sIL1RAcP) type. The brain exclusively expresses mIL1RAcP. SAM68 knockout results in remarkable conversion into sIL1RAcP in the brain, which significantly disturbs IL1RAcP neuronal function. Thus, we uncover the critical role of proper neuronal isoform selection through ALE choice by the SAM68-specific splicing program.
2019-12-29 | GSE110258 | GEO
Project description:We uncover a Sam68-dependent splicing program during cerebellar development. These events direct proper isoform expression of the genes required to guarantee the establishment of the correct spatial/temporal neural circuitry. The dysregulation in Sam68 null mice leads to functional defects in adult neurons
2020-06-01 | GSE133711 | GEO
Project description:The paralog RNA binding proteins (RBPs) Sam68 and SLM2 are co-expressed in the cerebral cortex and display very similar splicing activity. However, their relative function(s) in this context is unknown. By performing a time-course analysis, we found that these RBPs exhibit an opposite expression pattern during development. Sam68 expression declines postnatally while SLM2 increases after birth, and this developmental pattern is reinforced by hierarchical control of Sam68 expression by SLM2. Analysis of Sam68:Slm2 double knockout (Sam68:Slm2dko) mice revealed hundreds of exons that are sensitive to concomitant ablation of these proteins. Moreover, parallel analysis of single and double knockout cortices indicated that exons regulated mainly by SLM2 are characterized by a dynamic splicing pattern during development, whereas Sam68-dependent exons are spliced at relatively constant rates. Dynamic splicing of SLM2-sensitive exons is completely suppressed in the Sam68:Slm2dko developing cortex. Sam68:Slm2dko mice die perinatally with defects in neurogenesis and in neuronal differentiation, and the development of a hydrocephalus, consistent with splicing alterations in genes related to these biological processes. Thus, our study reveals that maintenance of the Sam68 and Slm2 paralog genes encoding homologous RBPs enables the orchestration of a dynamic splicing program while ensuring a robust redundant mechanism that supports proper cortical development.
2024-02-12 | GSE229749 | GEO
Project description: Not available
| S-EPMC8784167 | biostudies-literature
Project description:Cell type-specific alternative splicing during mammalian neuronal differentiation
| PRJNA380202 | ENA
Project description:The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain
| PRJNA139161 | ENA
Project description:Sam68 is a member of the STAR family of proteins that directly link signal transduction with post-transcriptional gene regulation. Sam68 controls the alternative splicing of many oncogenic proteins and its role is modulated by post-translational modifications, including serine/threonine phosphorylation, that differ at various stages of the cell cycle. However, the molecular basis and mechanisms of these modulations remain largely unknown. Here, we combined mass spectrometry, NMR spectroscopy, and cell biology techniques to provide a comprehensive post-translational modification (PTM) mapping of Sam68 at different stages of the cell cycle in HEK293 and HCT116 cells. We established that Sam68 is specifically phosphorylated at T33 and T317 by Cdk1, and demonstrated that these phosphorylation events reduce the binding of Sam68 to RNA, control its cellular localization, and reduce its alternative splicing activity, leading to a reduction in the induction of apoptosis and an increase in the proliferation of HCT116 cells.
2023-03-11 | PXD032716 | Pride
Project description:The metabolic conversion of oxidative phosphorylation to glycolysis provides tumor cells with energy and biosynthetic substrates, thereby promoting tumorigenesis and malignant progression. However, the mechanisms controlling the tumor metabolic switch is still not entirely clear. Here we demonstrate that SAM68 (gene name: KHDRBS1) as a splicing regulatory factor is frequently overexpressed in Lung adenocarcinoma (LUAD) and negatively correlated with the prognosis of LUAD patients. we find SAM68 promotes LUAD cells tumorigenesis and metastasis both in vitro and in vivo by regulating cancer metabolic switch. SAM68 drives cancer metabolism by mediating alternative splicing of Pyruvate kinase (PKM) pre-mRNAs, finally promoting the formation of PKM2. Mechanically, Sam68 interacted with the splicing repressor hnRNP A1, and depletion of hnRNP A1 or mutations that impair this interaction attenuated the PKM splicing regulation. Together, our work demonstrates key roles of SAM68 in the cancer metabolic conversion by regulating alternative splicing and SAM68 may be a promising therapeutic target for treating LUAD.This project looks into how SAM68 levels affect cancer cell phenotype in vitro
2020-11-04 | GSE149120 | GEO
Project description: Not available
| S-EPMC395764 | biostudies-literature
Project description: Not available
| S-EPMC4490682 | biostudies-literature