Cells are only able to work properly if they maintain a more or less constant balance of water and salts. In mammals, a hormone called arginine vasopressin regulates water and salt levels in the whole body. This hormone is made by cells in a region of the brain called the hypothalamus, and is then transported to the pituitary gland. When the level of water relative to the level of salts in the blood starts to drop (i.e., during dehydration), arginine vasopressin is released into the blood and travels to the kidneys where it acts as a signal to retain more water in the body.

However, if water levels continue to remain low, the stores of arginine vasopressin in the pituitary gland may run out and so more protein needs to be made in the hypothalamus. Like all proteins, arginine vasopressin is made by first copying a template encoded in a particular gene into a molecule called messenger ribonucleic acid (mRNA). During dehydration, the cells in the hypothalamus produce more of these corresponding mRNA molecules. Also, the mRNAs are slightly larger than normal because they have longer ‘polyA tails’ (structures added to the ends of all newly-made mRNAs). However, it was not clear how or why this happens.

Here, Konopacka et al. studied the production of arginine vasopressin in rats. The experiments show that a protein called Caprin-2 accumulates in hypothalamic neurons when rats are dehydrated. Furthermore, Caprin-2 is able to directly bind to the mRNA that encodes arginine vasopressin and is responsible for increasing the length of the polyA tail. To test whether this interaction is important for regulating the balance of water and salts, Konopacka et al. decreased the levels of Caprin-2 protein in the hypothalamus of live rats. When these rats became dehydrated, they had lower levels of the arginine vasopressin mRNA and these mRNAs had shorter polyA tails. Furthermore, the rats drank less water and urinated less than normal rats. Further experiments show that Caprin-2 helps to stabilize the structure of these mRNAs so that they accumulate in cells.

Together, Konopacka et al.'s findings show that Caprin-2 regulates the production of arginine vasopressin by interacting with and modifying its corresponding mRNA in the rat hypothalamus. The next challenge is to find out which other mRNAs in the hypothalamus are regulated by Caprin-2, and to determine their roles in the body.

The maintenance of salt and water homeostasis is a sine qua non condition for the survival of all living organisms (Antunes-Rodrigues et al., 2004). In mammals, this process is centrally regulated by the hypothalamo-neurohypophyseal system (HNS), the source of the antidiuretic neuropeptide hormone arginine vasopressin (AVP). The HNS consists of the large peptidergic magnocellular neurones (MCNs) of the hypothalamic supraoptic nuclei (SON) and paraventricular nuclei (PVN), the axons of which course though the internal zone of the median eminence and terminate on blood capillaries of the posterior pituitary (PP) gland (Bargmann, 1966; Burbach et al., 2001; Antunes-Rodrigues et al., 2004), a neuro–vascular interface through which the brain regulates peripheral organs in order to maintain homeostasis.

The biosynthesis of the AVP (Brownstein et al., 1980; Burbach et al., 2001) starts with the translation of AVP-encoding messenger ribonucleic acids (mRNAs) into a large precursor preprohormone that comprises a signal peptide (SP), the nine amino acid AVP moeity itself, the neurophysin II carrier molecule, and a C-terminal glycopeptide (copeptin) of unknown function. Delivery of AVP to the pituitary starts with the insertion of the preprohormone into the lumen of the endoplasmic reticulum with the removal of the SP. The resulting prohormone is folded then routed unidirectionally to the trans-Golgi network, where it is targeted specifically into the large dense core vesicle of the regulated secretory pathway. Whilst these granules are anterogradely transported some considerable distance towards the PP, the prohormone is processed to generate the biologically active, mature AVP, which is stored in PP axon terminals until mobilised for secretion into the systemic circulation. The rise in plasma osmolality that follows dehydration is detected by intrinsic MCN mechanisms (Bourque, 2008) and by specialised osmoreceptive neurons in the circumventricular organs such as the subfornical organ, which provide excitatory inputs to shape the firing activity of MCNs for hormone secretion (McKinley et al., 2004). Upon release, AVP travels through the blood stream to specific receptor targets located in the kidney where it promotes water reabsorption in the collecting duct (Breyer and Ando, 1994), and sodium reabsorption in the thick ascending limb of the loop of Henle (Ares et al., 2011).

As a consequence of the depletion of pituitary stores that accompanies a chronic osmotic stimulation, there is a need to synthesize more AVP. This starts with an increase in transcription (Murphy and Carter, 1990), which results in an increase in the abundance of both the precursor heteronuclear RNA (Kondo et al., 2004) and the mature mRNA (Sherman et al., 1986). In addition, following the onset of an osmotic challenge, the AVP mRNA is subject to a curious post-transcriptional modification in the form of an increase in the length of the 3′ poly(A) tail (Carrazana et al., 1988; Zingg et al., 1988; Carter and Murphy, 1989; Murphy and Carter, 1990). Until this report, the regulation and physiologiocal function of this poly(A) tail length increase were not understood.

In order to better understand the network of plastic events in the osmotically challenged SON and PVN, and in an attempt to identify novel regulatory players, we (Hindmarch et al., 2006) and others (Yue et al., 2006) have used microarrays to ask how chronic osmotic stress evokes changes in the transcriptome. One of the genes found to be differentially up-regulated in the SON and PVN was cytoplasmic activation/proliferation-associated protein-2 (Caprin2) (Mutsuga et al., 2004; Hindmarch et al., 2006; Yue et al., 2006), otherwise known as C1q domain containing 1 (C1qdc1), EEG1 and RNA granule protein 140 (RNG140). In these various guises, Caprin2 has been implicated in the inhibition of cell growth (Aerbajinai et al., 2004), differentiation (Aerbajinai et al., 2004; Lorén et al., 2009), the enhancement of canonical Wnt signaling (Ding et al., 2008; Miao et al., 2014; Flores and Zhong, 2015), and, as an RNA-binding protein, the maintenance of the dendritic structure in the adult vertebrate brain (Shiina and Tokunaga, 2010).

We sought to understand the physiological role of Caprin2 in the function related plasticity exhibited following an osmotic challenge. Specifically, given that Caprin2 is an RNA binding protein, we tested the hypothesis that it may associate with AVP transcripts and hence mediate changes in poly(A) tail length and/or mRNA stability.

We provide the first evidence that RNA binding protein Caprin-2 plays a critical role in mediating brain responses to osmotic stress. We show that Caprin-2 is expressed in AVP MCNs in the SON and PVN and that Caprin-2 expression in these neurons increases during osmotic stress. Importantly, we demonstrate that Caprin-2 knockdown in the SON and PVN disrupts physiological osmoregulatory mechanisms. Normally, chronic salt loading leads to a gradual increase of urine output and fluid intake. Loss of Caprin-2 significantly reduces the salt loading-induced urine output and fluid intake and increases urine osmolality, urine sodium concentration and plasma AVP levels.

We then explored the molecular mechanisms of Caprin-2 action in homeostatic osmoregulatory hypothalamic neuronal circuits. Caprin-2 has recently been identified in vitro as an RNA binding protein RNG140 (Shiina and Tokunaga, 2010). However, up until now, no specific RNA binding partners of Caprin-2 have been identified. Here we show that Caprin-2 binds to the AVP mRNA in the SON and PVN of EU and SL rats in vivo, and, in doing so, modulates both its abundance and poly(A) tail length.

By stimulating water retention at the level of the kidneys (Breyer and Ando, 1994), AVP plays a central role in the maintenance of cardiovascular homeostasis, particularly blood volume and osmolality (Antunes-Rodrigues et al., 2004). The increase in AVP biosynthesis in MCNs that follows osmotic stimulation is accompanied by a plethora of changes in gene expression (Mutsuga et al., 2004; Hindmarch et al., 2006; Yue et al., 2006). One of the novel genes identified as such by transcriptome analysis was Caprin-2. Here we confirm the transcriptome data, and that Caprin-2 protein is up-regulated at the mRNA level by chronic hyperosmotic cues. Using double immunostaining we also provide evidence that Caprin-2 protein is present in the cytoplasm of VP MCNs, and that its expression increases during osmotic stress. Caprin-2 has been reported to play a role in several physiological processes, including differentiation, apoptosis in erythroblasts or lens fiber cells, and synaptic plasticity in the mouse cerebellum (Aerbajinai et al., 2004; Ding et al., 2008; Lorén et al., 2009; Shiina and Tokunaga, 2010; Miao et al., 2014; Flores and Zhong, 2015). Although expression of Caprin-2 in the HNS has been reported (Mutsuga et al., 2004), its role in the maintenance of fluid homeostasis had not previously been addressed. We therefore investigated the physiological consequences of Caprin-2 gene knockdown using virally delivered specific shRNAs in the SON and PVN in vivo. The Caprin-2 shRNA had no effect on water homeostasis in euhydrated rats. In naïve rats (Greenwood et al., 2015), and in rats transduced with a scrambled control shRNA, as shown here, salt loading results in production of large amounts of dilute urine and excessive fluid intake. However, compared to the control animals, salt loaded Caprin-2 knockdown rats only minimally increased their urine production and they drank less fluid. Urine osmolality and sodium levels were also higher in Caprin-2 knockdown rats. These observations may be explained by water retention resulting from the elevated plasma AVP levels found in the Caprin-2 shRNA-transduced rats. Our data suggest that Caprin-2 knockdown rats increase their ability to concentrate urine and so doing they prevent the decrease in sodium excretion (i.e., elevation of plasma sodium) resulting from lower urine output by producing more concentrated urine.

We then explored the molecular mechanisms of Caprin-2 action in the hypothalamus, based on our hypothesis that this RNA binding protein (Shiina and Tokunaga, 2010) might associate with the AVP mRNA. Here we show that Caprin-2 does indeed bind to AVP mRNAs in the SON and PVN in vivo. We then asked if Caprin-2 binding has any role in the alterations in AVP mRNA metabolism that occur as a consequence of the chronic osmotic stimuli of dehydration or salt-loading, namely an increase in abundance (Sherman et al., 1986; Murphy and Carter, 1990), and the unusual post-transcriptional modification of an increase in the length of the 3′ poly(A) tail (Carrazana et al., 1988; Zingg et al., 1988; Carter and Murphy, 1989; Murphy and Carter, 1990). Our in vivo studies show that knockdown of Caprin-2 in the rat SON and PVN prevented the salt-loading-induced increases in the abundance of the AVP mRNA, and the elongation of its poly(A) tail. In HEK293T cells transfected with a plasmid containing rat AVP genomic sequences under constitutive CMV promoter, concomitant overexpression of Caprin-2 increased AVP mRNA abundance, whilst addition of the Caprin-2 shRNA significantly reduced AVP mRNA levels. At the same time, Caprin-2 overexpression resulted in elongation of the poly(A) tail of the AVP mRNA, whilst Caprin-2 knockdown shortened the poly(A) tails of the AVP mRNA. The direct binding and positive regulation of AVP transcript levels suggest that Caprin-2 may be important for stabilization of AVP mRNAs during osmotic stress, in a similar way to another AVP mRNA binding protein, poly(A)-binding protein (PABP) (Mohr et al., 2002). It is thus tempting to speculate that the two processes, increased poly(A) tail length and increased mRNA abundance, are consequential. An important role of poly(A) tail length in regulation of mRNA degradation and stability has been demonstrated for many transcripts (Curinha et al., 2014; Zhang et al., 2014). It is therefore possible that one of the functions of Caprin-2-mediated poly(A) tail length regulation is protection of AVP transcripts from degradation, which in turn would lead to the observed increase of AVP mRNA levels. Note that we are unable to distinguish between a process that promotes polyadenylation, or one that prevents deadenylation.

Unexpectedly, whilst Caprin-2 knockdown in the PVN and SON resulted in a decreased AVP mRNA levels in those structures, plasma AVP (peptide) levels increased. Although the precise mechanisms underlying this paradoxical effect require separate investigation, examination of the existing literature leads us to propose two possible hypotheses. Firstly, Caprin-2 binding to AVP mRNA might inhibit translation, a phenomenon observed as a consequence of other association mRNA-RNA-binding protein interactions, such as the binding of PABP to the AVP mRNA (Mohr et al., 2002; Richter, 2008). This is not necessarily in disagreement with the fact that Caprin-2 stimulates extension of poly(A) tail in AVP mRNAs—recent studies have revealed that a correlation between the length of poly(A) tail and translational activity is not always present (Weill et al., 2012; Subtelny et al., 2014).

It has been shown previously that recombinant Caprin-2 inhibits the translation of a luciferase mRNA in a cell-free rabbit reticulocyte lysate system (Shiina and Tokunaga, 2010). This is consistent with our observation that Caprin-2 knockdown in the SON and PVN increases circulating plasma AVP levels. It is conceivable that this effect results from the increased translation of AVP mRNA under conditions when Caprin-2 protein level is too low to suppress this process. Moreover, knockdown of Caprin-2, whilst increasing the translation of the AVP mRNA, might increase its turnover, and hence decreases steady state transcript levels and poly(A) tail length. We have previously examined the polysome distribution of the AVP mRNA in euhydrated and salt-loaded SON (Murphy and Carter, 1990), and showed no difference in the pattern association with heavy polysome fractions. However, the AVP mRNA is small, and subject to a high rate of translation, even in euhydrated animals. Thus, the rates of translation initiation, elongation and termination, none of which are directly measured by polysome analysis, especially when the size of the RNA limits ribosome number, could be influenced, positively or negatively, by poly(A) tail length. Quantification of Caprin-2 and AVP levels in AVP in the SON neurons (Figure 2) revealed that salt-loading elicits a significant increase in the former protein, but a significant decrease in the latter, consistent with Caprin-2 being an inhibitor of the translation of the AVP mRNA. However, it is important to point out the steady-state level of AVP in hypothalamic MCNs is not only determined by translation rate. As we describe in some detail in the Introduction, the AVP precursor is subject to axonal transport from cell bodies in the hypothalamus to terminals in the PP, a process that is activated by the need to deliver mature peptide to the circulation following an osmotic stimulus. Thus, further studies are needed to examine the translation of the AVP mRNA under different physiological conditions.

A second, but not mutually exclusive hypothesis is that the effects that we observe after Caprin-2 knockdown could be modulated by changes in dendritic release of AVP. Dendritic release and autocrine or paracrine action of AVP has been well documented (Ludwig and Stern, 2015). AVP released from dendrites inhibits the electrical activity of AVP neurons, thus suppressing axonal release to the blood stream (Ludwig and Stern, 2015). Caprin-2 protein is present in the RNA granules localized in the rat neuronal dendrites (Shiina and Tokunaga, 2010). Therefore, it is possible that Caprin-2 knockdown results in a decrease of the synthesis and dendritic release of AVP, which in turn decreases AVP-mediated auto-inhibition of AVP neurons and leads to an increase of AVP release in the neurohypophysis and increased plasma concentration, as we observe after Caprin-2 knockdown in the SON and PVN.

In this report, we have shown that, during an osmotic stimulus, three things happen to the AVP mRNA in the SON and PVN due to the action of Caprin-2: the abundance of Caprin-2 protein/AVP mRNA complexes increases, the AVP mRNA poly(A) tail elongates, and there is an increase in steady state levels of the AVP mRNA. On the basis of these data, we propose a new mechanism mediating the regulation of AVP gene expression (Figure 10). Whilst it has previously been demonstrated that a chronic osmotic stimulus results in an increase in the transcription of the AVP gene (Murphy and Carter, 1990), the data presented here provides new evidence that post-transcriptional process, governed by Caprin-2, are also operative. Both the transcriptional and the post-transcriptional mechanisms would contribute to overall steady-state AVP mRNA abundance. However, it would appear that the increase in AVP mRNA mediated by Caprin-2 does not result in an increase in AVP peptide production. Indeed, our results are consistent with previous reports that showed that Caprin-2 inhibits translation (Shiina and Tokunaga, 2010). Thus we suggest that association with Caprin-2 may inhibit the production of AVP peptide, perhaps by directly interfering with the translational apparatus, or through sequestration of AVP mRNA in translationally inert mRNP storage or transport granules (Buchan, 2014). Interestingly, polysome analysis revealed a heavy class of EDTA-resistant AVP mRNA containing fractions that might represent storage granules (Murphy and Carter, 1990). We also note that AVP transcripts are known to be transported to dendrites (Mohr et al., 2002) and to axons (Murphy et al., 1989), although in the latter case, the AVP RNAs are characterised by a short poly(A) tail that does not change in length following osmotic stimulation (Murphy et al., 1989).

Figure 10

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The osmotic status-dependent modulation of AVP mRNA poly(A) tail length in the SON and PVN was first described over 20 years ago (Carrazana et al., 1988; Zingg et al., 1988; Carter and Murphy, 1989), but only now, with the discovery of Caprin-2, do we have insight into the regulation and physiological function of this post-transcriptional process. To get a more comprehensive picture of Caprin-2 functioning in the HNS, it will be of interest to identify other mRNAs that bind to Caprin2 in the SON and PVN, in addition to those encoding AVP. Further, identification of the sequences within the AVP mRNA that are recognised by Caprin-2, and the Caprin-2 protein modules that mediate binding to the AVP mRNA and poly(A) tail extension, might reveal interactions with other known Caprin-2 functions, such as the modulation of Wnt signaling (Ding et al., 2008; Miao et al., 2014; Flores and Zhong, 2015) that may have regulatory and physiological relevance.

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Author details

1. Agnieszka Konopacka

   School of Clinical Sciences, University of Bristol, Bristol, United Kingdom

   Present address

   Neuroscience and Pain Research Unit, Pfizer, Cambridge, United Kingdom

   Contribution

   AK, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

2. Mingkwan Greenwood

   School of Clinical Sciences, University of Bristol, Bristol, United Kingdom

   Contribution

   MG, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

3. Su-Yi Loh

   Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

   Contribution

   S-YL, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

4. Julian Paton

   School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom

   Contribution

   JP, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

5. David Murphy

   1. School of Clinical Sciences, University of Bristol, Bristol, United Kingdom
   2. Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

   Contribution

   DM, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   d.murphy@bristol.ac.uk

   Competing interests

   The authors declare that no competing interests exist.

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