Motor coordination defects in mice deficient for the Sam68 RNA-binding protein

Lukong, Kiven Erique; Richard, Stéphane

doi:10.1016/j.bbr.2008.01.010

Cited by 44 publications

(41 citation statements)

References 34 publications

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“…Chl1 is a transmembrane cell adhesion receptor shown to promote neurite outgrowth and branching (23,42). Mice deficient in Chl1 display alterations in motor coordination (49), a defect recently associated with ablation of Sam68 in mice (35).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Sam68 Regulates a Set of Alternatively Spliced Exons during Neurogenesis

Chawla

Lin²,

Han

et al. 2009

Molecular and Cellular Biology

107

123

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Sam68 (Src-associated in mitosis, 68 kDa) is a KH domain RNA binding protein implicated in a variety of cellular processes, including alternative pre-mRNA splicing, but its functions are not well understood. Using RNA interference knockdown of Sam68 expression and splicing-sensitive microarrays, we identified a set of alternative exons whose splicing depends on Sam68. Detailed analysis of one newly identified target exon in epsilon sarcoglycan (Sgce) showed that both RNA elements distributed across the adjacent introns and the RNA binding activity of Sam68 are necessary to repress the Sgce exon. Sam68 protein is upregulated upon neuronal differentiation of P19 cells, and many Sam68 RNA targets change in expression and splicing during this process. When Sam68 is knocked down by short hairpin RNAs, many Sam68-dependent splicing changes do not occur and P19 cells fail to differentiate. We also found that the differentiation of primary neuronal progenitor cells from embryonic mouse neocortex is suppressed by Sam68 depletion and promoted by Sam68 overexpression. Thus, Sam68 controls neurogenesis through its effects on a specific set of RNA targets.Alternative splicing allows multiple functionally distinct mRNAs and proteins to be generated from a single gene, greatly enhancing the coding potential of the genome. Splicing patterns are controlled by RNA binding proteins that recognize specific splicing enhancer and silencer elements in the premRNA to alter spliceosome assembly, and variation in the expression of these proteins leads to tissue-specific exon use (5, 38). Splicing within a single cell can also be dynamically controlled by extracellular stimuli, although how this information is transmitted to splicing regulatory proteins is not yet known (55).Sam68 is a nuclear RNA binding protein implicated in various aspects of mRNA metabolism, including splicing, nuclear export, somatodendritic transport, and translation. Sam68 belongs to the family of GSG (GRP33, Sam68, GLD1) or STAR (signal transduction and activation of RNA) domain proteins. This domain includes a central KH (hnRNP K homology) RNA binding domain flanked by conserved N and C termini (36,54,59). The GSG domain in Sam68 binds to RNA motifs that are rich in A or U, such as UAAA or UUUA, and also mediates homodimerization (9, 31). Sam68 contains a variety of other protein domains that allow its interaction and modification by multiple signaling pathways. These many regulatory interactions and posttranslational modifications affect the RNA binding activity and localization of Sam68 and make it an appealing molecule for transducing information from signaling systems to pathways of mRNA metabolism (13,33,46,51,60).Sam68 is localized primarily in the nucleus as observed by immunofluorescence, consistent with its role in alternative splicing. Sam68 helps regulate the splicing of CD44 variable exon v5 in response to phosphorylation by extracellular signalregulated kinase in T lymphoma cells (39). Sam68 binds to exonic regulatory elements of v5 and cooperates wi...

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Section: Discussionmentioning

confidence: 99%

“…However, Sam68 null mice do not show a neurogenesis defect but instead show defects in bone mesenchymal cell differentiation (53). Only about onethird of Sam68 Ϫ/Ϫ mice survive to adulthood, with the survivors showing defects in motor coordination (35,53). Sam68 is widely expressed and plays roles in multiple cell types.…”

Section: Discussionmentioning

confidence: 99%

Sam68 Regulates a Set of Alternatively Spliced Exons during Neurogenesis

Chawla

Lin²,

Han

et al. 2009

Molecular and Cellular Biology

107

123

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“…Although expressed in multiple tissues, Sam68 expression is induced at sites of neurogenesis in mice (Lim et al 2006). Mice lacking Sam68 display motor coordination deficits and male sterility, suggesting that this factor is involved in aspects of neuronal function and fertility (Lukong and Richard 2008;Paronetto et al 2009). Given these intriguing phenotypes, it has been an important goal to identify the network of transcripts regulated by Sam68.…”

Section: Sam68mentioning

confidence: 99%

Networking in a global world: Establishing functional connections between neural splicing regulators and their target transcripts

Calarco¹,

Zhen²,

Blencowe³

2011

RNA

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Recent genome-wide analyses have indicated that almost all primary transcripts from multi-exon human genes undergo alternative pre-mRNA splicing (AS). Given the prevalence of AS and its importance in expanding proteomic complexity, a major challenge that lies ahead is to determine the functional specificity of isoforms in a cellular context. A significant fraction of alternatively spliced transcripts are regulated in a tissue-or cell-type-specific manner, suggesting that these mRNA variants likely function in the generation of cellular diversity. Complementary to these observations, several tissue-specific splicing factors have been identified, and a number of methodological advances have enabled the identification of large repertoires of target transcripts regulated by these proteins. An emerging theme is that tissue-specific splicing factors regulate coherent sets of splice variants in genes known to function in related biological pathways. This review focuses on the recent progress in our understanding of neural-specific splicing factors and their regulatory networks and outlines existing and emerging strategies for uncovering important biological roles for the isoforms that comprise these networks.

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“…The human genome encodes > 500 RBPs, each interacting with RNA with different affinities. 2 3,4 However, despite much progress in identifying alternative splicing events there is still much to uncover about the mechanisms governing specific exon usage in certain tissues and cell-types.…”

Section: Sam68 and Alternative Splicingmentioning

confidence: 99%

“…12 In addition, it was demonstrated that Sam68 was required for maintaining patterns of splicing even after differentiation had occurred. As Sam68 knockout mice exhibit defects in basal motor coordination, 4 the alterations in splicing patterns may partly contribute to this defect.…”

Section: Sam68 and Alternative Splicingmentioning

confidence: 99%