Pumilio2 deficient mice show a predisposition for epilepsy

Follwaczny, Philipp; Schieweck, Rico; Riedemann, Therese; Demleitner, Antonia Franziska; Straub, Tobias; Klemm, Anna H.; Bilban, Martin; Sutor, Bernd; Popper, Bastian; Kiebler, Michael

doi:10.1242/dmm.029678

Cited by 41 publications

(53 citation statements)

References 35 publications

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“…Despite multiple lines of evidence pointing to a key role of CPEBs in poly(A) changes in epilepsy reported here, we cannot however exclude a contribution of other RNABPs such as HUR or PUMILIO, which have previously been associated with epilepsy 39,40 . Similarly, among the various CPEBs, we show here that CPEB4 is a key player in epilepsy related poly(A)-dependent gene regulation, but we cannot discard that other CPEBs also play a role.…”

Section: Discussioncontrasting

confidence: 70%

Large-scale changes to mRNA polyadenylation in temporal lobe epilepsy

Parras

García

Alves

et al. 2019

Preprint

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34The molecular mechanisms that shape the gene expression landscape during the development 35 and maintenance of chronic states of brain hyperexcitability are incompletely understood. 36 Here we show that cytoplasmic mRNA polyadenylation, a posttranscriptional mechanism for 37 regulating gene expression, undergoes widespread reorganisation in temporal lobe epilepsy. 38 Specifically, over 25% of the hippocampal transcriptome displayed changes in their poly(A) 39 tail in mouse models of epilepsy, particular evident in the chronic phase. The expression of 40 cytoplasmic polyadenylation binding proteins (CPEB1-4) was found to be altered in the 41 hippocampus in mouse models of epilepsy and temporal lobe epilepsy patients and CPEB4 42 target transcripts were over-represented among those showing poly(A) tail changes. 43 Supporting an adaptive function, CPEB4-deficiency leads to an increase in seizure severity 44 and neurodegeneration in mouse models of epilepsy. Together, these findings reveal an 45 additional layer of gene expression control during epilepsy and point to novel targets for 46 seizure control and disease-modification in epilepsy. 47 48 49 50 51 52 53 54 55 56 57 58 59 Epilepsy is one of the most common chronic neurological disorders, affecting approximately 60 70 million people worldwide 1,2 . Temporal lobe epilepsy (TLE) is the most common 61 refractory form of epilepsy in adults and typically results from an earlier precipitating insult 62 that causes structural and functional reorganisation of neuronal-glial networks within the 63 hippocampus resulting in chronic hyperexcitability 3 . These network changes, which include 64 selective neuronal loss, gliosis and synaptic remodelling, are driven in part by large-scale 65 changes in gene expression 4-7 . The gene expression landscape continues to be dysregulated 66 once epilepsy is established 8 . 67 Recent studies have uncovered important roles for post-transcriptional mechanisms during 68 the development of epilepsy. These include the actions of small noncoding RNA, such as 69 microRNA and post-translational control of protein turnover via the proteasome contributing 70to altered levels of ion channels, changes in neuronal micro-and macro-structure and glial 71 responses within seizure-generating neuronal circuits 9-13 . The molecular mechanisms 72 underlying the transcriptional and translational landscape in epilepsy remain, however, 73 incompletely understood. 74In the cell nucleus, the majority of mRNAs acquire a non-templated poly(A) tail. Although 75 the addition of a poly(A) tail seems to occur by default, the subsequent control of poly(A) tail 76 length is highly regulated both in the nucleus and cytoplasm 14 . Cytoplasmic mRNA 77 polyadenylation contributes to the regulation of the stability, transport and translation of 78 mature transcripts, and is therefore an essential post-transcriptional mechanism for regulating 79 spatio-temporal gene expression 14 . 80The cytoplasmic polyadenylation element binding proteins (CPEBs) are ...

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Section: Discussioncontrasting

confidence: 70%

Large-scale changes to mRNA polyadenylation in temporal lobe epilepsy

Parras

García

Alves

et al. 2019

Preprint

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“…Mammalian Pum orthologs have crucial, diverse roles in growth and development, gametogenesis, hematopoiesis, neurogenesis, behavior, motor function and memory formation (97)(98)(99)(100)(101)(102)(103)(104)(105)(106). Their dysfunction has now been linked to cancer, neurodegeneration, epilepsy, memory impairment, reduced fertility, and developmental defects in mammals (97,98,100,103,(107)(108)(109)(110)(111). Thus, we anticipate that further elucidation of Pum function will facilitate better understanding of its role in development and disease, and perhaps inform future therapeutic interventions.…”

Section: The Mechanistic Insights Into Pum-mediated Repression Also Hmentioning

confidence: 99%

Unique repression domains of Pumilio utilize deadenylation and decapping factors to accelerate destruction of target mRNAs

Arvola

Chang

Buytendorp

et al. 2019

Preprint

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Pumilio is an RNA-binding protein that represses a network of mRNAs to control embryogenesis, stem cell fate, fertility, and neurological functions in Drosophila. We sought to identify the mechanism of Pumilio-mediated repression and find that it accelerates degradation of target mRNAs, mediated by three N-terminal Repression Domains (RDs), which are unique to Pumilio orthologs. We show that the repressive activities of the Pumilio RDs depend on specific subunits of the Ccr4-Not (CNOT) deadenylase complex. Depletion of Pop2, Not1, Not2, or Not3 subunits alleviates Pumilio RD-mediated repression of protein expression and mRNA decay, whereas depletion of other CNOT components had little or no effect. Moreover, the catalytic activity of Pop2 deadenylase is important for Pumilio RD activity. Further, we show that the Pumilio RDs directly bind to the CNOT complex. We also report that the decapping enzyme, Dcp2, participates in repression by the N-terminus of Pumilio. These results support a model wherein Pumilio utilizes CNOT deadenylase and decapping complexes to accelerate destruction of target mRNAs. Because the N-terminal RDs are conserved in mammalian Pumilio orthologs, the results of this work broadly enhance our understanding of Pumilio function and roles in diseases including cancer, neurodegeneration, and epilepsy.

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“…Indeed, treatments (genetic or pharmacological) that elevate dPum activity are potently anticonvulsive in Drosophila seizure mutants (Lin et al, 2017). Moreover, seizures in flies, rodents and human are associated with a decrease in dPum or Pum2 activity, respectively (Follwaczny et al, 2017, Lin et al, 2017, Siemen et al, 2011, Wu et al, 2015. Thus, whilst drug interventions that directly active Pum may be difficult to achieve in the clinic, inhibition of p300 may represent a more achievable route to better control epilepsy.…”

Section: Discussionmentioning

confidence: 99%

“…Despite a wide-ranging involvement in many aspects of CNS function, little is understood concerning the regulation of Pum expression in the CNS. Importantly, reduced levels of Pum have been linked to epilepsy in Drosophila, rodents and human (Follwaczny et al, 2017, Lin et al, 2017, Siemen et al, 2011, Wu et al, 2015.…”

Section: Introductionmentioning

confidence: 99%

Mef-2 and p300 interact to regulate expression of the homeostatic regulator Pumilio inDrosophila

Lin

Baines

2018

Preprint

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words)Pumilio (Pum) is a key component of neuron firing-rate homeostasis that maintains stability of neural circuit activity. Whilst Pum is ubiquitously expressed, we understand little about how synaptic excitation regulates its expression. Here, we characterised the Drosophila dpum promoter and identified multiple Myocyte enhancer factor-2 (Mef2)-binding elements. To understand the transactivation capability of dMef2, we cloned 12 dmef2 splice variants and used a luciferase-based assay to monitor dpum promoter activity. Whilst all 12 dMef2 splice variants enhance dpum promoter activity, exon 10-containing variants induce greater transactivation. Previous work shows dPum expression increases with synaptic excitation. However, we observe no change in dmef2 transcript in CNS exposed to picrotoxin (PTX). The lack of activity-dependence is indicative of additional regulation. We identified p300 as a likely candidate. We show that by binding to dMef2, p300 represses dpum transactivation. Significantly, p300 transcript is down-regulated by enhanced synaptic excitation (PTX) which, in turn, increases transcription of dpum through derepression of dMef2. These results suggest the activity-dependent expression of dpum is regulated by an interaction between p300 and dMef2.

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Pumilio2 deficient mice show a predisposition for epilepsy

Cited by 41 publications

References 35 publications

Large-scale changes to mRNA polyadenylation in temporal lobe epilepsy

Large-scale changes to mRNA polyadenylation in temporal lobe epilepsy

Unique repression domains of Pumilio utilize deadenylation and decapping factors to accelerate destruction of target mRNAs

Mef-2 and p300 interact to regulate expression of the homeostatic regulator Pumilio inDrosophila

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