Competitive regulation of alternative splicing and alternative polyadenylation by hnRNP H and CstF64 determines acetylcholinesterase isoforms

Nazim, Mohammad; Matsubara, Akio; Rahman, Mohammad Alinoor; Nasrin, Farhana; Takeda, Jun‐ichi; Ohe, Kenji; Ohkawara, Bisei; Ito, Mikako; Ohno, Kinji

doi:10.1093/nar/gkw823

Cited by 50 publications

(57 citation statements)

References 60 publications

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“…One function of τCstF-64 is to promote polyadenylation at proximal sites over distal sites [25, 65]. More specifically, a recent study demonstrated that CstF-64 cooperates with hnRNP H to regulate acetylcholinesterase isoforms in human neuronal cells [66], suggesting that τCstF-64 might play a similar role. Further, it has been shown that alternative 3′ exons participate in localization of mRNAs within neurons, for example to neural projections [67].…”

Section: Discussionmentioning

confidence: 99%

The Cstf2t Polyadenylation Gene Plays a Sex-Specific Role in Learning Behaviors in Mice

et al. 2016

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Polyadenylation is an essential mechanism for the processing of mRNA 3′ ends. CstF-64 (the 64,000 Mr subunit of the cleavage stimulation factor; gene symbol Cstf2) is an RNA-binding protein that regulates mRNA polyadenylation site usage. We discovered a paralogous form of CstF-64 called τCstF-64 (Cstf2t). The Cstf2t gene is conserved in all eutherian mammals including mice and humans, but the τCstF-64 protein is expressed only in a subset of mammalian tissues, mostly testis and brain. Male mice that lack Cstf2t (Cstf2t-/- mice) experience disruption of spermatogenesis and are infertile, although female fertility is unaffected. However, a role for τCstF-64 in the brain has not yet been determined. Given the importance of RNA polyadenylation and splicing in neuronal gene expression, we chose to test the hypothesis that τCstF-64 is important for brain function. Male and female 185-day old wild type and Cstf2t-/- mice were examined for motor function, general activity, learning, and memory using rotarod, open field activity, 8-arm radial arm maze, and Morris water maze tasks. Male wild type and Cstf2t-/- mice did not show differences in learning and memory. However, female Cstf2t-/- mice showed significantly better retention of learned maze tasks than did female wild type mice. These results suggest that τCstf-64 is important in memory function in female mice. Interestingly, male Cstf2t-/- mice displayed less thigmotactic behavior than did wild type mice, suggesting that Cstf2t may play a role in anxiety in males. Taken together, our studies highlight the importance of mRNA processing in cognition and behavior as well as their established functions in reproduction.

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Section: Discussionmentioning

confidence: 99%

The Cstf2t Polyadenylation Gene Plays a Sex-Specific Role in Learning Behaviors in Mice

et al. 2016

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“…Competition between CstF‐64 and hnRNP H (see Figure ) alters both polyadenylation and splicing in acetylcholinesterase and other transcripts in human neuron‐like cells (Nazim et al, ). Similarly, HuR/Elavl1 competes with CstF‐64 for binding to U‐rich sequences (H. Zhu, Zhou, Hasman, & Lou, ), which may have consequences in neuronal cells (K. Sun et al, ).…”

Section: Abundant Alternative Polyadenylation In the Brain Supports Nmentioning

confidence: 99%

Tissue‐specific mechanisms of alternative polyadenylation: Testis, brain, and beyond (2018 update)

MacDonald

2019

WIREs RNA

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Alternative polyadenylation (APA) is how genes choose different sites for 3′ end formation for mRNAs during transcription. APA often occurs in a tissue‐ or developmental stage‐specific manner that can significantly affect gene activity by changing the protein product generated, the stability of the transcript, its localization within the cell, or its translatability. Despite the important regulatory effects that APA has on tissue‐specific gene expression, only a few examples have been characterized mechanistically. In this 2018 update to our 2010 review, we examine mechanisms for the control of APA and update our understanding of the older mechanisms since 2010. We once postulated the existence of tissue‐specific factors in APA. However, while a few tissue‐specific polyadenylation factors are known, the emerging conclusion is that the majority of APA is accomplished by altering levels of core polyadenylation proteins. Examples of those core proteins include CSTF2, CPSF1, and subunits of mammalian cleavage factor I. But despite support for these mechanisms, no one has yet documented any of these proteins changing in either a tissue‐specific or developmental manner. Given the profound effect that APA can have on gene expression and human health, improved understanding of tissue‐specific APA could lead to numerous advances in gene activity control. This article is categorized under: RNA Processing > 3′ End Processing RNA in Disease and Development > RNA in Development

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“…First, alternative splicing of a single pre‐mRNA generates three different catalytic subunits called T, H, and R, which share a common N‐terminus and have specific C‐terminal peptides . The mechanisms regulating splicing choices have been partially decrypted . Second, AChE subunits are posttranslationally modified or associated with different peptides.…”

Section: The Origin Of Ache Deficiency In the Synaptic Cleftmentioning

confidence: 99%

Congenital myasthenic syndromes with acetylcholinesterase deficiency, the pathophysiological mechanisms

Legay

2018

Annals of the New York Academy of Sciences

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The neuromuscular junction (NMJ) is a cholinergic synapse in vertebrates. This synapse connects motoneurons to muscles and is responsible for muscle contraction, a physiological process that is essential for survival. A key factor for the normal functioning of this synapse is the regulation of acetylcholine (ACh) levels in the synaptic cleft. This is ensured by acetylcholinesterase (AChE), which degrades ACh. A number of mutations in synaptic genes expressed in motoneurons or muscle cells have been identified and are causative for a class of neuromuscular diseases called congenital myasthenic syndromes (CMSs). One of these CMSs is due to deficiency in AChE, which is absent or diffuse in the synaptic cleft. Here, I focus on the origins of the syndrome. The role of ColQ, a collagen that anchors AChE in the synaptic cleft, is discussed in this context. Studies performed on patient biopsies, transgenic mice, and muscle cultures have provided a more comprehensive view of the connectome at the NMJ that should be useful for understanding the differences in the symptoms observed in specific CMSs due to mutated proteins in the synaptic cleft.

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Competitive regulation of alternative splicing and alternative polyadenylation by hnRNP H and CstF64 determines acetylcholinesterase isoforms

Cited by 50 publications

References 60 publications

The Cstf2t Polyadenylation Gene Plays a Sex-Specific Role in Learning Behaviors in Mice

The Cstf2t Polyadenylation Gene Plays a Sex-Specific Role in Learning Behaviors in Mice

Tissue‐specific mechanisms of alternative polyadenylation: Testis, brain, and beyond (2018 update)

Congenital myasthenic syndromes with acetylcholinesterase deficiency, the pathophysiological mechanisms

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