The role of CELF proteins in neurological disorders

Gallo, Jean‐Marc; Spickett, Corinne M.

doi:10.4161/rna.7.4.12345

Cited by 40 publications

(30 citation statements)

References 70 publications

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“…These factors have been implicated in neurological disorders and in CUG trinucleotide expansion diseases such as myotonic dystrophy (Cooper et al 2009;Gallo and Spickett 2010). These factors are also involved in several aspects of mRNA metabolism, including AS (Ladd et al 2001;Ho et al 2004).…”

Section: Additional Neural-specific Splicing Regulatorsmentioning

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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Section: Additional Neural-specific Splicing Regulatorsmentioning

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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“…In contrast, it was demonstrated that the decay of Nmu transcript seems to be determined by as-yet-uncharacterized sequence motifs in the 3=-UTR of the transcript that is able to recruit mRNA degradation machinery. Based on the presence of CUG-repeated sequences located in the 3=-UTR of Nmu mRNA, we have previously tested the effect of CUG-binding protein 1, a member of RNA-binding proteins capable of regulating mRNA decay and RNA splicing (14), on Nmu mRNA degradation. However, there was no observed change in mRNA stability in pCRE-Luc-Nmu 3=- Fig.…”

Section: E806mentioning

confidence: 99%

Ovarian regulation of neuromedin U and its local actions in the ovary, mediated through neuromedin U receptor 2

Lin¹,

Wu²,

Lee³

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Lin TY, Wu FJ, Lee WY, Hsiao CL, Luo CW. Ovarian regulation of neuromedin U and its local actions in the ovary, mediated through neuromedin U receptor 2. Am J Physiol Endocrinol Metab 304: E800-E809, 2013. First published February 19, 2013 doi:10.1152/ajpendo.00548.2012.-Neuromedin U (NMU) was originally identified as an anorexigenic peptide that modulates appetite as well as energy homeostasis through the brain-gut axis. Although growing evidence has linked NMU activity with the development of female reproductive organs, no direct expression of and function for NMU in these organs has been pinpointed. Using a superovulated rat model, we found that NMU is directly expressed in the ovary, where its transcript level is tightly regulated by gonadotropins. Ovarian microdissection and immunohistochemical staining showed clearly that NMU is expressed mainly in theca/interstitial cells and to a moderate extent in granulosa cells. Primary cell studies together with reporter assays indicated the Nmu mRNA level in these cells is strongly induced via cAMP signaling, whereas this increase in expression can be reversed by the degradation message residing within its 3=-untranslated region, which recruits cis-acting mRNA degradation mechanisms, such as the gonadotropininduced zinc finger RNA-binding protein Zfp36l1. This study also demonstrated that NMUR2, but not NMUR1, is the dominant NMU receptor in the ovary, where its expression is restricted to theca/ interstitial cells. Treatment with NMU led to induction of the early response c-Fos gene, phosphorylation of extracellular signal-regulated kinase 1/2, and promotion of progesterone production in both developing and mature theca/interstitial cells. Taken as a whole, this study demonstrates that NMU and NMU receptor 2 compose a novel autocrine system in theca/interstitial cells in which the intensity of signaling is tightly controlled by gonadotropins. adenosine 3=,5=-cyclic monophosphate; theca/interstitial cells NEUROMEDIN U (NMU) is a neuropeptide first isolated from the porcine spinal cord and was named based on its strong ability to cause uterine muscle contraction (31). Following its initial isolation, NMU has been subsequently identified in rats (7, 30), frogs (9), chickens (33), humans (2), and other vertebrates (5) with a diverse length due to there being different locations for its endoproteolytic sites in each propeptide. Despite this, mature NMU peptides across species display a remarkable amino acid identity in their COOH-terminal pentapeptide (Phe-ArgPro-Arg-Asn-NH 2 ), suggesting that this region is important to receptor binding and biological activity (37).NMU has not been detected in circulating blood, and therefore it has been proposed to act more as a local regulator than as a circulating hormone (8). Distribution of NMU was later reported to be ubiquitous, with higher expression in the pituitary gland, gastrointestinal tract, thyroid gland, ovary, and spinal cord (8,11). In contrast to this wide distribution, the two NMU receptors, NMUR1 and NMUR2, show ...

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“…The expanded RNA sequesters RNA splicing factors including members of the muscle-blind-like family of proteins, MBNL 1, 2, and 3 (Miller et al, 2000), disrupting their normal subcellular distribution, and usurping their function. In addition, there is pathological upregulation of another RNA-binding protein and alternative splicing factor CUG-binding protein 1 (Gallo and Spickett, 2010). These RNA splicing factors are involved in the alternative splicing of the muscle-specific chloride channel (Kino et al, 2009), insulin receptor (Paul et al, 2006), and cardiac troponin-T (Warf and Berglund, 2007) transcripts; thereby providing a unifying molecular substrate for the seemingly disparate multisystemic manifestations including myopathy, insulin resistance, cardiac conduction defects, respectively.…”

Section: The Prominence Of Rna-binding Proteins In Age-related Neurodmentioning

confidence: 99%

Structural disorder and the loss of RNA homeostasis in aging and neurodegenerative disease

Gray¹,

Woulfe²

2013

Front. Genet.

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Whereas many cases of neurodegenerative disease feature the abnormal accumulation of protein, an abundance of recent literature highlights loss of RNA homeostasis as a ubiquitous and central feature of pathological states. In some diseases expanded repeats have been identified in non-coding regions of disease-associated transcripts, calling into question the relevance of protein in the disease mechanism. We review the literature in support of a hypothesis that intrinsically disordered proteins (proteins that lack a stable three dimensional conformation) are particularly sensitive to an age-related decline in maintenance of protein homeostasis. The potential consequences for structurally disordered RNA-binding proteins are explored, including their aggregation into complexes that could be transmitted through a prion-like mechanism. We propose that the spread of ribonucleoprotein complexes through the nervous system could propagate a neuronal error catastrophe at the level of RNA metabolism.

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The role of CELF proteins in neurological disorders

Cited by 40 publications

References 70 publications

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

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

Ovarian regulation of neuromedin U and its local actions in the ovary, mediated through neuromedin U receptor 2

Structural disorder and the loss of RNA homeostasis in aging and neurodegenerative disease

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