The Role of Dynamic miRISC During Neuronal Development

Abstract

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.

Modulation of miRISC-Mediated Gene Silencing in Eukaryotes

“…The reversibility of translational repression modulated by RBPs and miRISCs allows for flexible control of the expression of targeted genes in a wide pool of mRNAs in a timely manner. This is, as mentioned earlier, important in cases such as cellular stress, cellular growth, or proliferation as well as during cellular specification (Nawalpuri et al, 2020). In some cases, "interruptions" in translation induced by miRISC and RBPs translational control will be enough to buffer cellular stress or developmental transition states.…”

“…miRNAs employ their silencing function mostly through translational repression and mRNA decay ( Braun et al, 2012 ; Djuranovic et al, 2011 ; Fabian and Sonenberg, 2012 ; Bartel, 2018 ). While the exact mechanism of silencing remains a topic of debate, the “default” mechanism agreed upon includes inhibition of translation, followed by deadenylation, decapping, and decay of the mRNA transcript, as shown in Figure 2A ( Djuranovic et al, 2011 ; Braun et al, 2013 ; Gardiner et al, 2015 ; Nawalpuri et al, 2020 ). Even though research has shown translational repression occurs first and might be one mode of controlling gene expression, it is the mRNA decay that ultimately consolidates and silences the target mRNAs ( Bazzini et al, 2012 ; Bêthune et al, 2012 ; Djuranovic et al, 2011 ; Hu and Coller, 2012 ).…”

“…The factors that make miRISC variations are associated with cell types as well as cellular processes such as cellular stress, growth, and differentiation. The heterogeneity of the miRISC complex allows for diversity in its function ( Sheu-Gruttadauria and MacRae, 2017 ; Dallaire et al, 2018 ; Nawalpuri et al, 2020 ). The different cell-specific cofactors will contribute to the miRISC function, potentially changing the function of the same miRNA-Ago complex depending on the cell type.…”

“…This can be done through recruitment of the miRISC to the binding site on the target mRNA (example of Smaug and FUS above) or the binding of the RBP can change the secondary structure of the mRNA to increase the binding accessibility for the miRISC. Pumilio, a member of the Puf family, is an RBP that has been shown to enhance miRISC activity through unwinding the mRNA 3′UTR, thus promoting miRISC binding ( Kedde et al, 2010 ; Miles et al, 2012 ; Nawalpuri et al, 2020 ). Pumilio is known to promote cell-cycle re-entry of quiescent cells upon binding to the 3′UTR of the mRNA that encodes for the tumor suppressor p27.…”

Distinct temporal expression of GW182 in neurons regulates dendritic arborization

“…Interestingly, many of these RBPs such as FMRP, Pumilio, MOV10, and CPEB act as ancillary components of miRNA induced silencing complex (miRISC) to regulate miRNA mediated gene silencing (Ford et Filipowicz et al, 2008). These protein components associate to form functionally diverse miRISC complexes (Nawalpuri et al, 2020). The imperfect complementarity between metazoan miRNA-mRNA pairs prevents the endonucleolytic action of AGO2, causing the requirement for additional factors for effective miRNA mediated gene silencing.…”