Opinion

The multifunctional Staufen proteins:

conserved roles from neurogenesis to

synaptic plasticity

1 2

Jacki E. Heraud-Farlow and Michael A. Kiebler

1

Department of Chromosome Biology, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria

2

Department of Anatomy and Cell Biology, Ludwig-Maximilians-University, 80336 Munich, Germany

Staufen (Stau) proteins belong to a family of RNA- Stau-mediated asymmetric cell division during

binding proteins (RBPs) that are important for RNA neurogenesis

localisation in many organisms. In this review we During cell division, cellular components are distributed

discuss recent findings on the conserved role played equally between daughter cells to ensure faithful replica-

by Stau during both the early differentiation of neurons tion and expansion of the given cell type. In specialised

and in the synaptic plasticity of mature neurons. Recent cases, however, asymmetric distribution is used to gener-

molecular data suggest mechanisms for how Stau2 ate daughter cells with different cell fates [5]. The division

regulates mRNA localisation, mRNA stability, transla- of the Drosophila neuroblast during neurogenesis has

tion, and ribonucleoprotein (RNP) assembly. We offer a served as an ideal model system in which to study asym-

perspective on how this multifunctional RBP has been metric cell division. It was during this process that the role

adopted to regulate mRNA localisation under several of Stau in neurogenesis was first uncovered (Box 1).

different cellular and developmental conditions. Until recently, however, the role of Stau proteins in

mammalian neurogenesis had not been investigated. Two

RNA localisation in the CNS new papers now show that Stau2 makes a crucial contri-

The localisation of RNA to distinct regions of the cell bution to cell fate specification during neurogenesis in mice

allows restricted protein synthesis, leading to spatially [6,7]. Neurogenesis commences at around embryonic day

controlled adaptations within the cell. This is achieved 13 (E13), when asymmetric cell division of radial glial cells

through the actions of an ensemble of proteins (and (RGCs) begins, producing another RGC and either an

probably regulatory ncRNAs) which direct the fate of intermediate progenitor cell (IPC) or a post-mitotic neuron

mRNAs via nuclear export, mRNA stability, transport, (Figure 1B). RGCs are the founder cells for a large propor-

and translational control [1]. This fundamentally impor- tion of the neurogenic lineages in the CNS and thus are of

tant process can be envisaged to be performed by a fundamental importance to brain development [8]. At this

dynamic molecular machine [2] that is utilised many times time, Stau2 starts to polarise in mitotic cells both in vitro

throughout development. In neurons, many RNAs are and in vivo where it localises to the differentiating cell [7].

localised to both the axon and dendrites where their This is consistent with Drosophila Stau, which also segre-

protein products modify the local compartment; for gates into the differentiating GMC.

example, the growth cone during axon outgrowth or an Short hairpin RNA (shRNA)-mediated knockdown of

individual synapse during memory formation [3]. Disrup- Stau2 both in vitro and in vivo results in an 50% decrease

tion of this process may have severe consequences because in the number of Pax6 (paired box 6)-positive RGCs, and a

mutations in RBPs with known roles in local translation concomitant two- to threefold increase in the number of

have been linked to several human neurologic diseases [4]. more differentiated daughter cells [6,7]. This is therefore

We discuss here new data pertaining to the function of consistent with premature neuronal differentiation in the

Stau-containing RNPs during RNA localisation in the absence of Stau2. Associated with an increase in the

nervous system. In the past decade Stau proteins have number of neurons is defective migration of the excess

emerged as crucial regulators of several aspects of neuron neurons to the cortical plate. It is unclear, however, wheth-

development and function (Box 1). er this is the result of an intrinsic defect in migration of the

neurons or the loss of their scaffold – which is normally

provided by the long fibres of the now depleted RGCs

(Figure 1B).

Corresponding author: Kiebler, M.A. ([email protected]). If Stau2 were responsible for segregating cell fate deter-

Keywords:

RNA localisation; Staufen; neurogenesis; synaptic plasticity; RNP; mRNA minants then, in its absence, both daughter cells should

stability; learning and memory.

receive those factors, which would promote differentiation

0166-2236/

and suppress the stem cell state. What then are these

ß 2014 The Authors. Published by Elsevier Ltd. This is an open access article under

putative cell fate determinants? Interestingly, the mRNA

the CC BY license (http://creativecommons.org/licenses/by/3.0/). http://dx.doi.org/

10.1016/j.tins.2014.05.009 encoding the homologue of Drosophila pros, prospero

470 Trends in Neurosciences, September 2014, Vol. 37, No. 9

Opinion Trends in Neurosciences September 2014, Vol. 37, No. 9

Box 1. A short history of Stau proteins in the brain

The Stau family of double-stranded RNA-binding proteins (dsRBPs) Mammals express two orthologues of Stau, Stau1 and Stau2, and

exhibit a conserved function in RNA localisation, which is supported both exist in several splice isoforms [49,83,84]. Stau1 is expressed in

by data in Drosophila, Xenopus, Aplysia, zebrafish, and mouse most cell types, including neurons, whereas Stau2 is enriched in the

[18,28,69,70,73,78] (see Figure 1 in main text). Stau was originally brain and only expressed at low levels in other tissues. The two

described for the localisation of mRNAs encoding cell fate determi- proteins are predominantly found in distinct particles in dendrites of

nants essential for the anterior–posterior patterning of the Drosophila primary rodent hippocampal neurons, suggesting they may have

oocyte (see Figure 1A in main text) [69,79]. However, mutants in distinct functions (see Figure 1C in main text) [84]. Studies of Stau1-

Drosophila stau also affect brain development and function [13,69,80]. and Stau2-deficient neurons now also support this view (see main

During Drosophila neuroblast mitosis, Stau mediates the asymmetric text). In the first functional studies in mammalian hippocampal

localisation of prospero (pros) mRNA to the future ganglion mother neurons, knockdown of Stau2 resulted in fewer, extended dendritic

cell (GMC), away from the neuroblast, thus promoting differentiation spines compared to controls, which corresponds to a reduction in the

[81]. In the GMC, the Pros transcription factor is a crucial cell fate number of synapses [18]. These changes also lead to a reduction in

determinant that acts to promote GMC fate (differentiation) and miniature excitatory postsynaptic current (mEPSC) amplitudes,

suppress the stem cell fate [82]. The GMC then goes on to divide once indicating a defect in synaptic transmission through postsynaptic

more to produce two neurons. New data now indicate that this role in glutamate receptors. Stau1 is also important for mammalian neuronal

fly neurogenesis is conserved in the mammalian brain (see main text). morphogenesis and plasticity, although in apparently non-redundant

Early work from the laboratory of Tully then showed Drosophila pathways to Stau2 [19,21,22].

Stau is also important in the adult brain. One-day memory is Recent studies in both Drosophila and mammalian neurons have

abolished when temperature sensitive stau mutants are shifted to now extended these early studies, uncovering roles of Stau proteins

the non-permissive temperature immediately after training that in dendrite morphogenesis, plasticity, and memory formation. The

induces long-term memory (LTM), suggesting an early role for stau mRNAs and molecules that underlie the adult brain Stau phenotypes

in LTM formation [13]. In addition, Stau is required for long-term are beginning to be uncovered, and these suggest that Stau1 and

facilitation of Aplysia motor neurons in response to serotonin, Stau2 are not only involved in RNA transport but also in mRNA

indicating that roles in plasticity are not limited to flies [78]. stability and translation (see main text).

homeobox 1 (Prox1), was also associated with Stau2 in the to promote neuronal cell fate – where one common link is

mouse brain as it is in the fly (also Box 1). Together with the localisation of functionally related mRNAs via Stau.

two other common ribonucleoprotein particle (RNP) com-

ponents, Pum2 and Ddx1, the Stau2/Prox1 complex is Stau proteins in synaptic plasticity and memory

asymmetrically distributed [6]. Pum2 is also associated formation

with Stau2 in mature neurons and colocalises with Stau2 A growing suite of evidence now shows that Stau proteins

in dendrites of mature hippocampal neurons [9]. This are not only important for neurogenesis during early de-

suggests that it too represents another conserved compo- velopment but that they also play another important func-

nent of the RNA localisation machinery in both neurogen- tional role in the mature nervous system. Data from

esis and synaptic plasticity (Figure 2). Kusek et al. (2012) Drosophila, Aplysia, and mouse all indicate a conserved

additionally found that Stau2 affects the asymmetric role in dendrite development, synapse function, and plas-

distribution of Trim32 and Bbs2 mRNA [7]. Trim32 is ticity (Box 1).

the mouse homologue of Drosophila Brat, whose protein In the fly, Stau is required in the adult brain during

also asymmetrically localises in fly neuroblasts [10]. long-term memory (LTM) formation [13–17]. Stau expres-

Furthermore, Trim32 has previously been shown to sion is induced under conditions of LTM formation via the

regulate neurogenesis in mice [11]. In progenitor cells, NMDA receptor, which leads to its CREB (cAMP response

the apically localised Prox1 mRNA is translationally element binding protein)-dependent transcription [13,16].

repressed because Prox1 protein is absent from these cells Not only is one-day memory abolished in temperature-

[6]. The authors therefore propose that upon asymmetric sensitive stau mutants [13], but a genetic interaction

cell division repression is relieved allowing expression of between FMRP (fragile X mental retardation protein)

Prox1 and other cell fate determinants (Figure 2A). and Stau in the formation of one-day memory in double

In summary, it is fair to conclude that Stau2 is impor- heterozygote flies implies the role of these two RBPs in this

tant for distributing cell fate determinants that then sup- process is related [14]. A recent study now also demon-

press the stem cell state and promote differentiation. The strates the importance of stau in the activity-dependent

findings that Stau2 regulates Prox1 and Trim32 (Brat structural plasticity of Drosophila larval motor neuron

homologue) suggest that specific mRNAs may be conserved dendrites [17]. In this case, neuronal activity leads to

2+

between fly and mouse neurogenesis. These transcription the CaMKII (Ca /calmodulin-dependent protein kinase

factors promote neurogenesis via different mechanisms. II)-dependent phosphorylation of the transcription factor

The former is via relief of notch1 inhibition on neurogen- Adf1 (Adh transcription factor 1), which then negatively

esis [12], whereas the latter is partly via the enhancement regulates the expression of stau in motor neurons. In the

of the activity of several microRNAs [11]. Furthermore, context of Adf1 induction, Stau acts as a negative regulator

Kusek et al. found that Stau2 associates with multiple of dendritic growth. However, it should be noted that both

mRNAs encoding components related to cilia function and knockdown and overexpression of Stau reduced dendritic

signaling. Regulation of these transcripts could lead to the outgrowth of larval motor neurons, suggesting a more

differential response of daughter cells to extracellular complex relationship between Stau and dendritic out-

ligands, and this is another known means to achieve growth [17].

different cell fates during asymmetric cell division [7]. In rodent primary hippocampal neurons, Stau2 con-

Therefore, different mechanisms are likely to act in concert tributes to dendritic spine morphogenesis, the sites of

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Opinion Trends in Neurosciences September 2014, Vol. 37, No. 9

(A) Embryonic development Drosophila oocyte Drosophila egg

bcd

A osk P A P

(B) Neurogenesis

Basal

IPC Neuron Dividing RGC Pax6+ Indirect + neurogenesis Tbr

Direct neurogenesis RGC Apical

(C) Synapc development and plascity

Key: Staufen proteins Microtubules RNP components

Motor proteins mRNAs

TRENDS in Neurosciences

Figure 1. Staufen (Stau) proteins have conserved functions during three stages of development. (A) Stau proteins have a conserved role in early embryonic development

(see main text). Depicted here is the localisation of Drosophila Stau in the oocyte and egg. Stau is crucial for the localisation of oskar (osk) mRNA to the posterior (P) pole of

the oocyte (left side) and bicoid (bcd) mRNA to the anterior (A) pole of the egg (right side). The orange shading indicates the localisation of Stau protein. (B) During mouse

+

neurogenesis, radial glial cells (RGCs; Pax6 ) divide asymmetrically to produce another RGC and a post-mitotic neuron (‘direct neurogenesis’). In the case of ‘indirect

+

neurogenesis’ the RGC produces another RGC and an intermediate progenitor cell (IPC; Tbr ), which divides once more symmetrically to produce two neurons. During

maturation, the neurons migrate along the RGC fibre away from the apical surface towards the cortical plate (‘basal’). Stau2 protein (orange shading) localises into the

differentiating cell (IPC or neuron), promoting differentiation and suppressing the stem cell state (see also Figure 2A). Stau is also important during Drosophila

neurogenesis where it localises cell fate determinants into the differentiating ganglion mother cell (GMC). (C) Homologues of Stau in Drosophila, Aplysia, and rodents have

functions in synaptic development and plasticity. The somatodendritic localisation of Stau2 protein (orange dots) is depicted here in a mature neuron. The protein forms

RNPs with mRNAs and other proteins that traffic bidirectionally along microtubules in dendrites. Stau proteins are involved in memory formation and plasticity, and are

believed to contribute to the transport and activity-dependent translation of localised mRNAs (see Figure 2B).

excitatory synapses (Box 1) [18]. In addition, in older that is associated with internalisation of AMPA receptors

neurons Stau2 is required for metabotropic glutamate and a weakening of synapses in response to synaptic

receptor (mGluR)-induced protein synthesis-dependent activity [20].

long-term depression (LTD) (Figures 1 and 2) [19]. This Although orthologous, Stau1 and Stau2 seem to have

phenotype is independent of its role in dendritic spine non-redundant functions in mature neurons. This is prob-

morphogenesis [19]. LTD is a form of synaptic plasticity ably due to the targeting of different mRNAs and different

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Opinion Trends in Neurosciences September 2014, Vol. 37, No. 9

(A) Neurogenesis Dividing RGC Developing neurons

Translaon repressed Translaon acve Ddx1 Stau2 Pum2 Stau2 ? Pum2 Ddx1 AAAn AAAn E.g., Prox1, Trim32 E.g., Prox1, Trim32

Differenaon Differenaon Stem cell state Stem cell state

(B) Synapc plascity

AMPAR

mGluR Receptor internalisaon

‘LTD proteins’

CBP80 Stau2 Pum2 FMRP RNP disassembly/ miRISC translaon E.g., Rgs4, Map1b

TRENDS in Neurosciences

Figure 2. Molecular models for the role of Staufen 2 (Stau2) during neurogenesis and in synaptic plasticity. Two models are presented for Stau2 function in (A) developing

and (B) mature neurons. Some components of the ribonucleoproteins (RNPs) may be shared between the two developmental processes (e.g., Pum2, pumilio RNA-binding

family member 2), whereas others are specific [e.g., Ddx1, DEAD (Asp-Glu-Ala-Asp) box helicase 1]. Likewise, there may be some mRNA targets that are common across

development (e.g., Rgs4, regulator of G-protein signaling 4), whereas others are temporally and spatially specific. (A) Model of Stau2 RNP function during neurogenesis.

Stau2 forms RNPs in dividing radial glial cells (RGCs) with the RBPs, Ddx1 and Pum2, as well as with mRNAs, and these segregate into the differentiating daughter cell

[intermediate progenitor cell (IPC) or neuron; Figure 1]. mRNAs found in these RNPs include Prox1 (prospero homeobox 1) and Trim32 (tripartite motif containing 32). These

are believed to be translationally repressed in the dividing RGC because the Prox1 protein is not expressed in the progenitors (left side). Following segregation, the mRNAs,

which encode cell fate determinants, are translated and act to promote differentiation and suppress the stem cell state (right side). It has not yet been determined whether

Stau2 remains associated with the transcripts in neurons during translation or is removed. (B) Model for Stau2 function during group 1 metabotropic glutamate receptor

(mGluR) long-term depression (LTD). Stau2 RNPs are localised near synapses. Stau2 interacts and colocalises with the nuclear cap-binding protein (CBP80) and the

translational repressors FMRP (fragile X mental retardation protein) and Pum2 in dendrites of mature neurons. In addition, Stau2 interacts with components of miRISC

(miRNA-induced silencing complex) in the brain. Signalling through mGluRs leads to translation of localised mRNAs, which encode so-called ‘LTD proteins’. These

contribute to the endocytosis of AMPA receptors (AMPARs), resulting in depression of the synapse. The complement of mRNAs required for LTD has not yet been

determined. We propose here that Stau2 RNPs are disassembled/remodelled following synaptic stimulation, allowing translation of target mRNAs, such as Rgs4 and Map1b

(microtubule associated protein 1B), which contribute to the modification of the ‘activated’ synapse. FMRP knockout mice exhibit enhanced mGluR-LTD, whereas Stau2

knockdown impairs LTD, therefore the two proteins may have antagonistic effects.

mechanisms of action on those targets (discussed below). In Stau2 knockdown neurons Stau1-deficient mice exhibit a

contrast to Stau2, knockdown of Stau1 by small interfering decrease in dendritic protrusions, which in turn appear to be

RNAs (siRNAs) in hippocampal slice cultures impairs the elongated, resulting in fewer synapses [22]. Additionally,

chemically induced NMDA receptor-dependent late form Stau1 mutant neurons show impaired dendritic outgrowth

of long-term potentiation (L-LTP), but not the early form, [22]. Again, the effect of Stau1 on L-LTP is independent of its

nor LTD [21]. This type of synaptic plasticity is also effect on dendritic spine morphology. However, both the

transcription- and translation-dependent, but results in a morphological as well as the electrophysiological effect

strengthening of synaptic connections. Similarly to are mediated via the NMDA receptor [23]. Despite the

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Opinion Trends in Neurosciences September 2014, Vol. 37, No. 9

morphological defects of the Stau1 mutant mice in synapse reasonable to hypothesise that misregulation of synaptic

development, only a deficit in locomotor activity has been proteins encoded by target mRNAs underlies the described

detected in vivo, whereas learning and memory formation Stau protein phenotypes.

appears to be normal [22]. Importantly, Stau2 is not mGluR-dependent LTP and LTD both require new

upregulated in the Stau1 mutant mice, arguing against a protein synthesis. For LTD, the model assumes that, upon

compensatory mechanism between the two paralogues [22]. stimulation of a particular synapse, mGluR-mediated

However, redundancy or compensation by other genes signaling leads to the derepression and translation of

during development cannot be ruled out, especially given localised mRNAs encoding ‘LTD’ proteins. (Figure 2B)

that Stau1 and Stau2 have been reported to heterodimerise, [32]. To date only a handful of LTD proteins have been

at least in some cell lines [24]. In summary, both proteins are described, including Map1b. The theory is that they encode

involved in dendritic spine morphogenesis, and this seems proteins that contribute to the endocytosis of AMPA recep-

to be independent of the effects on plasticity [19,23]. In tors and the depression of the synapse. It is therefore likely

addition, Stau1 and Stau2 appear to have non-redundant that the newly identified Stau2 target mRNAs encoding

functions in protein synthesis-dependent forms of L-LTP synaptic proteins represent additional LTD proteins that

and LTD at hippocampal synapses, respectively. contribute to this phenomenon.

What are the molecular functions of Stau proteins in Towards an understanding of the molecular machine

synaptic plasticity? that guides RNA localisation

Together, the aforementioned results demonstrate the im- In the Drosophila oocyte, Stau has been implicated in the

portance of Stau proteins for several forms of protein syn- transport [33], anchoring [33–35] and translation activa-

thesis-dependent synaptic plasticity in different organisms. tion [36,37] of the oskar mRNA to the posterior pole. It is

What is less clear is the underlying molecular causes for also crucial for the localisation of the bicoid mRNA to the

these defects in Stau mutants. Is misregulation of individual anterior pole of the oocyte [38]. In both cases, once local-

Stau target mRNAs responsible for the defects in plasticity? ised, Stau protein stays associated with the mRNA

Or are many mRNAs misregulated in the absence of Stau1/2 throughout anchoring and translation, suggesting roles

that collectively lead to defects at the synapse? in all of these processes [39].

Several studies have estimated the number of mRNAs The general model for RNA localisation posits that an

associated with Stau2 in the brain or cell lines to be mRNA is packaged with proteins into RNPs in the nucleus,

approximately 1200 different mRNAs [7,25,26]. The and the complex is then exported to the cytoplasm and

number of physiologically relevant targets that are directly transported in a translationally silent state to its destina-

regulated by Stau2 is, however, likely to be much smaller tion where translation can be activated [1]. RNPs are

[27]. For example, these studies isolated total RNA from thought to undergo remodelling because proteins can be

Stau2 RNPs, and these may include mRNAs bound by added or removed at all points. In neurons, new in vivo

other RBPs within the particle. Furthermore, of the imaging data indicates that mRNAs and ribosomes are

1200 mRNAs associated with Stau2 in embryonic rat ‘unmasked’ in response to synaptic activity [40,41]. This

brain, the steady-state levels of only 38 were influenced unmasking refers to increased accessibility to the mRNA

by Stau2 downregulation in neurons (discussed below) by probes, and this is thought to correlate with a degran-

[27]. However, there may be more functionally relevant ulation of RNPs that allows increased mRNA translation

targets where Stau2 regulates localisation and/or transla- in response to stimuli [40,41]. Following translation, the

tion but not steady-state mRNA levels, for example. localisation process eventually ends with the decay of the

Studies in rodents indeed suggest roles in localisation mRNA, presumably locally at the synapse. In this context,

that are independent of an effect on mRNA stability. In Stau proteins are likely to contribute to several distinct

hippocampal neurons, both Stau proteins form RNPs that steps of the localisation process.

traffic in neurons to distal dendrites via microtubules

[18,28]. Expression of a dominant-negative Stau2 in neu- Stau proteins and translational control

rons reduces total dendritic RNA by 40%, while concomi- Recent work has identified the complement of proteins and

tantly increasing the somatic RNA levels [29]. Consistent RNAs present in Stau2 granules in the brain, yielding

with this, the vast majority of Stau2 coprecipitating mRNAs better understanding of Stau2 function [9,26,27,31,42].

from rat brain are localised in the neuropil layer of the Our laboratory has used biochemical fractionation of en-

hippocampus – a layer which is dense in neuronal processes dogenous brain lysates to remove (rough) endoplasmic

and devoid of cell bodies [27,30]. reticulum (ER)-associated Stau2 from the input material

Interestingly, the identified 38 functional targets were to identify Stau2 interactors from the non-membrane

highly enriched for synaptic proteins, suggesting that bound pool of Stau2 [9]. In this work, two different neuro-

Stau2 does indeed regulate biologically related mRNAs nal RNPs (Barentsz and Stau2) were compared; this pro-

[27]. Of these, mRNAs encoding proteins with known roles vided evidence that transcripts are translationally

in synaptic plasticity and behaviour were identified, repressed during transport. Importantly, a series of known

including the regulator of G-protein signaling 4 (Rgs4) translational repressors are enriched in the Stau2 RNPs,

and complexin 1 (Cplx1). In addition, the Camk2a (Stau1), including FMRP, Pura (purine-rich element binding

microtubule associated protein 1B/Map1b (Stau2), and protein A), and DDX6 [DEAD (Asp-Glu-Ala-Asp) box

b-actin/Actb (Stau2) mRNAs have been implicated in helicase 6, also known as Rck], as well as several compo-

transport by the Stau homologues [18,19,31]. It is therefore nents of the RNA-induced silencing complex (RISC) [9].

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Opinion Trends in Neurosciences September 2014, Vol. 37, No. 9

Consistent with these observations, there was no enrich- up-frameshift 1 (Upf-1) to elicit mRNA decay [55]. Stau2

ment of translation initiation factors. Further supporting was also recently implicated in SMD in human cells [24].

translational repression is the findings that the nuclear Physiologically, SMD contributes to the differentiation of

proteins CBP80 (cap binding protein 80) and PABPN1 myoblasts, the motility of keratinocytes and the differen-

(polyadenylate binding protein 1, nuclear) were both iden- tiation of adipocytes [56–58].

tified in the Stau2 RNPs [9]. First, this provides evidence We recently reported the impact of Stau2 downregulation

that the complexes are initially assembled in the nucleus. on target mRNAs in primary cortical neurons [27]. Interest-

Second, the presence of CBP80 and PABPN1, together with ingly, 32 of the associated mRNAs were downregulated,

the absence of eIF4E (eukaryotic translation initiation fac- whereas six were upregulated following Stau2 knockdown.

tor 4E), suggest that translation is stalled because they are This suggests that Stau2 preferentially mediates the stabi-

normally replaced by eIF4E once steady-state translation is lisation of target mRNAs rather than their destabilisation

established [43]. Interestingly, however, given that the exon [27]. Several new studies also support the findings from

junction complex (EJC) seems to be largely absent from neurons, showing Stau-mediated stabilisation in HEK293F

Stau2 RNPs, it may be that the mRNAs have undergone a cells, neuroblastoma cells and myoblasts [59–61]. In

first round of translation [9]. On the other hand, there is one notable example, the long non-coding RNA (lncRNA)

some evidence that the EJC component eIF4AIII is present terminal differentiation-induced ncRNA (TINCR) guides

in Stau2 particles, raising the possibility that it is involved Stau1 to target mRNAs through a complementary 25 nt

in an EJC-independent function in this case [9]. In this sequence in the lncRNA and mRNA (Box 2) [62]. This

context, eIF4AIII has previously been shown to regulate association leads to the stabilisation of the mRNA. Such

the expression of the Arc (activity regulated cytoskeletal- an elegant mechanism would provide a way to direct Stau

associated protein) mRNA in dendrites, leading to changes proteins to subsets of mRNAs in different tissues through

in synaptic strength [44]. Likewise, the presence of CBP80 regulated expression of specific lncRNAs.

and PABPN1 may be independent of their known role in the Together, these studies suggest that cell type-specific

initial round of translation. It should also be noted that differences exist with regard to the effect of Stau proteins

although CBP80 and PABPN1 are present in Stau2 gran- on target mRNA stability. Stau1 and Stau2 interact di-

ules, it remains to be shown directly that all proteins are rectly with Upf1 in an RNA-independent manner in human

indeed present on an individual mRNA. However, CBP80 cells [24]. By contrast, in embryonic rat brain this interac-

and Stau2 do partially colocalise in distal dendrites of tion appears to be RNA-dependent [9], providing one pos-

hippocampal neurons [9]. sible explanation for the different effects on mRNA

As mentioned above, an association of Stau proteins stability between different cell types, given that Upf1 is

with the rough ER and ribosomes has been well documen- crucial for SMD. On the other hand, a new study which

ted, indicating a link to translation [45–48]. Biochemical investigated the global profile of Stau1 binding in human

fractionation and immunofluorescence of Stau2 in hippo- cells and the impact of Stau1 downregulation could find

campal neurons suggests that there might be (at least) two little evidence for destabilisation of target mRNAs, which

pools of the protein: one associated with the rough ER that would be expected for SMD [48]. In conclusion, these

is part of large complexes and mostly immobile, and a studies highlight the need for further investigation into

soluble fraction in smaller mobile RNPs that are found in the impact of Stau proteins on mRNA stability to deter-

distal dendrites [45,49]. The larger complexes cofraction- mine how both stabilisation and destabilisation might be

ate with ribosomal and ER markers, whereas the smaller controlled and under what physiological conditions these

complexes do not. Consistent with a role in translation, it regulatory events occur.

was recently shown that Stau1 associates with actively

translating ribosomes in human cells [48]. These findings Are Stau proteins important for RNP assembly?

fit with previous publications that link Stau1 to ribosomes New advances into how non membrane-bound RNP gran-

and translation [50–52]. ules assemble suggest that the Stau proteins may be

It remains to be seen how Stau targets are translationally involved. Several new papers from the McKnight labora-

regulated once localised. The use of high-resolution imaging tory provide compelling evidence that low complexity (LC)

has recently shed some light on this area. Experiments polypeptide sequences can reversibly polymerise into uni-

in which endogenous mRNAs were labelled and tracked form amyloid-like fibres to form the structural basis for

following depolarisation of neurons indicate that RNP gran- many types of cellular RNA granules, such as neuronal

ules disassemble in response to activity, allowing transla- transport granules, stress granules, and P-bodies [63]. LC

tion to proceed [40,41]. In the future, it will be interesting sequences are protein domains composed of amino acids

to use such imaging techniques to see how Stau proteins with very little diversity. These reports extend previous

are regulated during neuronal activity and whether they studies showing that LC sequences are important for

influence granule assembly or translational control. localising RBPs to P-bodies in yeast and to stress granules

in mammalian cells [64–66]. The authors propose that LC

Stau proteins and mRNA stability sequences, which are especially enriched in nucleic acid-

In cell lines, mammalian Stau1 has been reported to target binding proteins, can exist in one of three states: (i) soluble

mRNAs for degradation via a process termed Staufen- proteins, (ii) dynamic and reversible polymerised fibres,

mediated decay (SMD) [53,54]. SMD is a translation- and (iii) irreversible insoluble aggregates (as seen in some

dependent decay pathway where Stau1 binds to target pathologies [63]). Interestingly, Stau1 was one of the 106

0

3 -untranslated regions (UTRs) and recruits the helicase RBPs precipitated with the granules from all four different

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Opinion Trends in Neurosciences September 2014, Vol. 37, No. 9

Box 2. Stau-recognised structures (SRS)

Stau proteins belong to the large family of dsRBPs which bind mammals because it was also enriched in rodent Stau2-stabilised

specifically to double-stranded RNA (dsRNA; as opposed to dsDNA target mRNAs [27].

or single-stranded nucleic acids) via dsRNA-binding domains

Figure IB Formation of intramolecular structures within long non-

(dsRBDs) [85]. New studies detail the numerous possibilities for

coding RNAs (lncRNAs).

the formation of secondary structures that are recognised by Stau

proteins. Recently, the TINCR lncRNA was found to associate with Stau1 in

differentiating keratinocytes [62]. An independent region of TINCR

base-pairs with complementary mRNAs, thus recruiting Stau1 to

Figure IA Intramolecular structures formed in cis within an mRNA

molecule. the mRNA to mediate its stabilisation. The structure within the

0 lncRNA was not yet precisely defined.

The 3 -UTR of the SMD target, ARF1 (ADP-ribosylation factor 1),

requires a 19 bp stem-loop for regulation by Stau1; however, 0

Figure IC Intermolecular base-pairing between the 3 -UTRs of two

similar structures could not be found in other SMD targets [53]. mRNAs.

0

A new study found that the open reading frames (ORFs) and 3 - 0

Alu elements within the 3 -UTRs of two mRNAs can additionally

UTRs of Stau1 targets have a high overall secondary structure or

form double-stranded structures that are recognized by Stau1 in

high GC content in human cell lines [48].

human cells. This can result in the degradation of both mRNAs via

In addition, Stau1 targets are enriched for two inverted Alu

SMD, provided that both are translated [88].

elements which can fold to form a long dsRNA structure. This is

recognized by Stau1 and can enhance their nucleocytoplasmic Figure ID Intermolecular base-pairing between a lncRNA and an

export [48,86,87]. mRNA.

In Drosophila, genome-wide screening identified three dsRNA A Stau1 SRS can be formed when highly complementary short

structures that were enriched in Stau targets [75]. The double- interspersed elements (SINEs, e.g., Alu) within a lncRNA and an mRNA

stranded regions were formed in cis, and have only a small number interact to produce long dsRNA structures [56,89]. The interaction of

of mismatched bases, zero or few unpaired bases, and short the two RNAs and binding of Stau1 results in decay of the mRNA via

internal loops. One of these structures appears to be conserved in SMD.

Intra-molecular Inter-molecular

mRNA (A) lncRNA (B) mRNA + mRNA (C) lncRNA+mRNA (D)

mRNA lncRNA ′ Stau Stau 3 5′ 3′ 5′ 3′ lncRNA Stau Stau Stau Stau 5′ mRNA Alu Alu/SINE 5′ 3′ 5′ 3′ 5′ 3′ mRNA 5′ mRNA Alu mRNA mRNA Stau

3′ Alu

TRENDS in Neurosciences

Figure I. Diversity of Staufen-recognised structures.

tissues or cell types tested (NIH-3T3, mouse ES cells, polymerise different sets of proteins into a unique RNA

mouse brain, and mouse testis) [63]. This suggests that granule to achieve its cellular fate. Whether the LC

Stau proteins contain LC sequences that polymerise to domains of Stau proteins are indeed important for RNP

form granules in many different cell and tissue types, formation and dynamics is an interesting prospect that

validating its classification as an important RNP compo- warrants further investigation.

nent. Rewardingly, the mRNA components of Stau2 gran-

ules identified in rat brain [27] significantly overlap with Concluding remarks

mRNAs precipitated in the LC-domain granules from Early work established a conserved function of Stau pro-

mouse brain [67], arguing that they are the same RNPs. teins in embryonic development in species ranging from

The formation of LC-domain fibres is dependent on a flies to frogs, pigs and zebrafish [69–74]. As discussed here,

high local concentration of protein, and can represent the conservation of Stau protein functions clearly extend

homo- or heterotypic fibres consisting of one or many beyond the embryo to neurogenesis and synaptic develop-

LC-containing proteins. It is likely that, in vivo, RNA ment and plasticity (Figure 1). It is therefore fair to con-

sequences provide the scaffold to create a high local con- clude that Stau is a common factor in the RNA localisation

centration of the RBP to polymerise the LC domains. In a machinery that is utilised by different cell types under

biological sense, this observation would fit with the ‘RNA different conditions.

signature’ model of post-transcriptional regulation [68] This raises many questions about how mRNA target

where cis-elements in an mRNA guide the binding of selection changes and how this is regulated (Box 2; further

multiple different RBPs and trans-acting factors. In this outstanding questions are given in Box 3). In this respect,

case, the RNA would provide the local environment to recent studies have indicated that a thorough approach to

476

Opinion Trends in Neurosciences September 2014, Vol. 37, No. 9

Box 3. Outstanding questions

(i) Molecular roles of Stau proteins

(ii) Physiological functions of Stau proteins

How is translation regulated in Stau2 RNPs? Are ribosomes

How are Stau proteins regulated by neuronal activity? In

associated with the RNPs during transport or only once

Drosophila, stau is transcriptionally induced under conditions

localised? How is ribosome association regulated?

of long-term memory formation. Although it has been reported

Do Stau proteins regulate the dynamics of neuronal RNA

in mammals that Stau1 and Stau2 are important for LTP and

granule assembly/disassembly via their LC domains?

LTD, respectively, it has not been determined how the RBPs

Is RNP assembly regulated by post-translational modifications

respond to these induction protocols. How does neuronal

of RBPs, for example phosphorylation, as was suggested for the

activity influence RNP assembly/disassembly?

RBP FUS (fused in sarcoma)?

What is the underlying cause of the defects in LTP and LTD seen

How do Stau proteins regulate both mRNA stabilisation and

in Stau1 and Stau2 knockdown, respectively? Can the mis-

destabilisation? What are the differences between mRNAs that

regulation of specific mRNAs be linked to these defects? Do

are targeted for one fate versus the other?

Stau proteins truly regulate mRNA expression locally at the

Both mammalian Stau homologues are expressed in multiple

synapse in response to synaptic activity?

isoforms. Do different isoforms have distinct or overlapping

How does the repertoire of Stau2 target mRNAs change during

functions in neurons? How are these functions affected by post-

different stages of development? Embryonic RGCs give rise to

translational modifications?

neurons, whereas postnatal RGCs give rise to various glial

When and where are RNPs formed and how are they

populations. Is Stau2 also important for gliagenesis as well as

remodelled over time? The identification of nuclear proteins in neurogenesis?

the Stau2 RNPs indicates that these are initially formed in the

What is the phenotype of Stau2 knockout mice? Are there

nucleus. It remains unclear at which stage during RNP assembly

defects in learning and memory formation? Are there any

different proteins are recruited.

effects akin to neurodevelopmental or neuropsychiatric dis-

How do Stau proteins recognize dsRNA structures of varying

orders? Can different developmental effects in the brain be

lengths? Structural studies looking at the interaction between

distinguished, for example as a result of defects in neurogenesis

Stau dsRBDs and natural targets are necessary to determine the

or defects in the plasticity of mature neurons?

requirements of target recognition.

What lncRNAs are associated with Stau proteins in different cell

types? Do the lncRNAs guide Stau to different target mRNAs as

is the case for the TINCR lncRNA in keratinocytes?

the manuscript. This work was supported by the Austrian Science Funds

identifying targets is necessary [27,75]. The expression

(I590-B09, SFB F43), the European Science Foundation (ESF) program

level of Stau proteins can have a large impact on how

RNAQuality (I 127-B12), and a Human Frontier Science Program (HFSP)

many mRNAs are bound and identified, and even modest

network grant (RGP24/2008).

overexpression of Stau can lead to the identification of

10-fold more (probably spurious) targets [75]. This obser-

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