Splice form‐dependent regulation of axonal arbor complexity by FMRP

Zimmer, Stephanie; Doll, Steven G.; Garcia, A. Denise R.; Akins, Michael R.

doi:10.1002/dneu.22453

Cited by 15 publications

(20 citation statements)

References 55 publications

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“…A recent study has shown that although FMRP is present throughout the brain, its expression varies markedly among different neuronal populations (Zorio et al, 2017). Within a given neuron, FMRP localizes to the soma, developing and mature axons, dendrites, and the base of dendritic spines (Antar et al, 2004(Antar et al, , 2006Ferrari et al, 2007;Zimmer et al, 2017). Because neurons are so highly polarized, transport of mRNAs along the axon and dendrites to undergo local, on-site protein synthesis is key for maintaining proper structural and functional polarity (Bramham, 2008;Cioni et al, 2018;Rangaraju et al, 2017;Tom Dieck et al, 2014).…”

Section: Fmrp At Synapsesmentioning

confidence: 99%

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

Bagni

Zukin

2019

Neuron

267

258

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Altered synaptic structure and function is a major hallmark of fragile X syndrome (FXS), autism spectrum disorders (ASDs), and other intellectual disabilities (IDs), which are therefore classified as synaptopathies. FXS and ASDs, while clinically and genetically distinct, share significant comorbidity, suggesting that there may be a common molecular and/or cellular basis, presumably at the synapse. In this article, we review brain architecture and synaptic pathways that are dysregulated in FXS and ASDs, including spine architecture, signaling in synaptic plasticity, local protein synthesis, (m)RNA modifications, and degradation. mRNA repression is a powerful mechanism for the regulation of synaptic structure and efficacy. We infer that there is no single pathway that explains most of the etiology and discuss new findings and the implications for future work directed at improving our understanding of the pathogenesis of FXS and related ASDs and the design of therapeutic strategies to ameliorate these disorders. ASDs and FXS: Causes and Clinical Features Approximately 1%-3% of the general population is affected by intellectual disabilities (IDs). IDs are neurodevelopmental disorders defined by significant limitations in intellectual functioning and adaptive behaviors and often exhibit comorbidity with autism (Mefford et al., 2012). Autism spectrum disorders (ASDs) are characterized by high phenotypic heterogeneity, comprising deficits in social interaction and communication as well as repetitive and stereotyped behaviors (

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Section: Fmrp At Synapsesmentioning

confidence: 99%

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

Bagni

Zukin

2019

Neuron

267

258

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“…Fragile X mental retardation protein has been implicated as a regulator of synaptic plasticity and thereby learning and memory (reviewed in Bostrom et al, 2016 ). The functions of FMRP in nervous system have been related to the control of synaptic protein synthesis in response to neurotransmitter activation and affecting the formation of axonal and dendritic structures ( Feng et al, 1997 ; Greenough et al, 2001 ; Weiler et al, 2004 ; Zimmer et al, 2017 ). The FMRP-mediated regulation of mRNA translation has been also directly linked to neurotransmitter receptor systems involved in synaptic plasticity.…”

Section: Introductionmentioning

confidence: 99%

Reduced Levels of the Synaptic Functional Regulator FMRP in Dentate Gyrus of the Aging Sprague-Dawley Rat

Šmidák

Sialana

Kristofova

et al. 2017

Front. Aging Neurosci.

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Fragile X mental retardation protein (FMRP) encoded by Fragile X mental retardation 1 (FMR1) gene is a RNA-binding regulator of mRNA translation, transport and stability with multiple targets responsible for proper synaptic function. Epigenetic silencing of FMR1 gene expression leads to the development of Fragile X syndrome (FXS) that is characterized by intellectual disability and other behavioral problems including autism. In the rat FXS model, the lack of FMRP caused a deficit in hippocampal-dependent memory. However, the hippocampal changes of FMRP in aging rats are not fully elucidated. The current study addresses the changes in FMRP levels in dentate gyrus (DG) from young (17 weeks) and aging (22 months) Sprague – Dawley rats. The aging animal group showed significant decline in spatial reference memory. Protein samples from five rats per each group were analyzed by quantitative proteomic analysis resulting in 153 significantly changed proteins. FMRP showed significant reduction in aging animals which was confirmed by immunoblotting and immunofluorescence microscopy. Furthermore, bioinformatic analysis of the differential protein dataset revealed several functionally related protein groups with individual interactions with FMRP. These include high representation of the RNA translation and processing machinery connected to FMRP and other RNA-binding regulators including CAPRIN1, the members of Pumilio (PUM) and CUG-BP, Elav-like (CELF) family, and YTH N(6)-methyladenosine RNA-binding proteins (YTHDF). The results of the current study point to the important role of FMRP and regulation of RNA processing in the rat DG and memory decline during the aging process.

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“…All these studies indicate that it is not miRNA alone, but the composition of miRISC has a great significance in the pathophysiology of disorders of the nervous system. There is Bhattacharyya, 2016, 2018) FMRP (Castren et al, 2005;Tervonen et al, 2009;Callan et al, 2010;Saffary and Xie, 2011;Jeon et al, 2014) TRIM-32 (Brat, mei-P26,NHL-2) (Bello, 2006;Betschinger et al, 2006;Lee et al, 2006;Bowman et al, 2008;Neumüller et al, 2008;Hammell et al, 2009;Schwamborn et al, 2009;Loewen et al, 2018) Hu Proteins (Marusich et al, 1994;Dobashi et al, 1998;Kasashima et al, 1999;Anderson et al, 2000;Akamatsu et al, 2002Akamatsu et al, , 2005Perrone-Bizzozero and Bolognani, 2002;Kraushar et al, 2014) Pumilio (Burow et al, 2015;Zahr et al, 2018) ESCRT Factors FMRP (Dockendorff et al, 2002;Ivanco and Greenough, 2002;Morales et al, 2002;Michel, 2004;Pan et al, 2004;Li, 2009;Doll and Broadie, 2015;Wang et al, 2015;Zimmer et al, 2017;Shen et al, 2019) MOV10 (Skariah et al, 2017) Pumilio (Menon et al, 2004(Menon et al, , 2009Ye et al, 2004;Vessey et al, 2010;...…”

Section: Discussionmentioning

confidence: 99%

The Role of Dynamic miRISC During Neuronal Development

Nawalpuri

Ravindran

Muddashetty

2020

Front. Mol. Biosci.

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Activity-dependent protein synthesis plays an important role during neuronal development by fine-tuning the formation and function of neuronal circuits. Recent studies have shown that miRNAs are integral to this regulation because of their ability to control protein synthesis in a rapid, specific and potentially reversible manner. miRNA mediated regulation is a multistep process that involves inhibition of translation before degradation of targeted mRNA, which provides the possibility to store and reverse the inhibition at multiple stages. This flexibility is primarily thought to be derived from the composition of miRNA induced silencing complex (miRISC). AGO2 is likely the only obligatory component of miRISC, while multiple RBPs are shown to be associated with this core miRISC to form diverse miRISC complexes. The formation of these heterogeneous miRISC complexes is intricately regulated by various extracellular signals and cell-specific contexts. In this review, we discuss the composition of miRISC and its functions during neuronal development. Neurodevelopment is guided by both internal programs and external cues. Neuronal activity and external signals play an important role in the formation and refining of the neuronal network. miRISC composition and diversity have a critical role at distinct stages of neurodevelopment. Even though there is a good amount of literature available on the role of miRNAs mediated regulation of neuronal development, surprisingly the role of miRISC composition and its functional dynamics in neuronal development is not much discussed. In this article, we review the available literature on the heterogeneity of the neuronal miRISC composition and how this may influence translation regulation in the context of neuronal development.

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Splice form‐dependent regulation of axonal arbor complexity by FMRP

Cited by 15 publications

References 55 publications

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

Reduced Levels of the Synaptic Functional Regulator FMRP in Dentate Gyrus of the Aging Sprague-Dawley Rat

The Role of Dynamic miRISC During Neuronal Development

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