A Novel Look at Astrocytes: Aquaporins, Ionic Homeostasis, and the Role of the Microenvironment for...

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The Neuroscientist19(2) 195 –207© The Author(s) 2012Reprints and permission: http://www. sagepub.com/journalsPermissions.navDOI: 10.1177/1073858412447981http://nro.sagepub.com

Reviews

Introduction

Since their discovery about 26 years ago (Benga and others 1986; Denker and others 1988; Preston and others 1992), water channels (aquaporins, AQPs) have been identified in most body tissues (Verkman and Mitra 2000). At least 13 AQPs (numbered 0–12) have been identified so far in mammals, some of them expressed in various isoforms (King and others 2004). In this review, we focus on the main water channel of the vertebrate brain, AQP4. Although first discovered in the brain (Jung and others 1994) AQP4 was subsequently localized in many other organs (Brown and others 1995; Mobasheri and others 2007) as summarized in more detail below.

Aquaporins are integral membrane proteins spanning the lipid bilayer six times with three extracellular and two intracellular loops (Jung and others 1994). Conserved through evolution, they all form tetramers facilitating water movements across the membrane (Ishibashi and oth-ers 2011; Tani and others 2009; Walz and others 2009). AQP4 is known to form higher order complexes that can

be detected by freeze-fracture electron microscopy dis-playing rectangular clusters of membrane molecules (Rash and others 1998; Wolburg and others 2011). In fact, these orthogonal arrays of particles (OAPs) had been described and investigated before aquaporins became known. Only later it was shown that OAPs consist of, or at least contain AQP4 molecules, and their formation depended on iso-form expression levels (Furman and others 2003; Rash and others 1998). Thus, at locations where OAPs have been described, it can be taken for the occurrence of AQP4, but not the other way around, that is, AQP4 can occur without the formation of OAPs. It should be mentioned that it is not known whether the water transport capacity is different in

447981 NROXXX10.1177/1073858412447981Mack and WolburgThe Neuroscientist

1Institute of Anatomy, University of Tübingen, Tübingen, Germany2Institute of Pathology and Neuropathology, University of Tübingen, Tübingen, Germany

Corresponding Author:Andreas F. Mack, Institute of Anatomy, University of Tübingen, Österbergstraße 3, D-72074 Tübingen, Germany Email: [email protected]

A Novel Look at Astrocytes: Aquaporins, Ionic Homeostasis, and the Role of the Microenvironment for Regeneration in the CNS

Andreas F. Mack1 and Hartwig Wolburg2

Abstract

Aquaporin-4 (AQP4) water channels are located at the basolateral membrane domain of many epithelial cells involved in ion transport and secretion. These epithelial cells separate fluid compartments by forming apical tight junctions. In the brain, AQP4 is located on astrocytes in a polarized distribution: At the border to blood vessels or the pial surface, its density is very high. During ontogeny and phylogeny, astroglial cells go through a stage of expressing tight junctions, separating fluid compartments differently than in adult mammals. In adult mammals, this barrier is formed by arachnoid, choroid plexus, and endothelial cells. The ontogenetic and phylogenetic barrier transition from glial to endothelial cells correlates with the regenerative capacity of neuronal structures: Glial cells forming tight junctions, and expressing no or unpolarized AQP4 are found in the fish optic nerve and the olfactory nerve in mammals both known for their regenerative ability. It is hypothesized that highly polarized AQP4 expression and the lack of tight junctions on astrocytes increase ionic homeostasis, thus improving neuronal performance possibly at the expense of restraining neurogenesis and regeneration.

Keywords

glia, tight junction, AQP4, blood-brain barrier, phylogeny

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196 The Neuroscientist 19(2)

OAP-bound AQP4 compared with AQP4 molecules not arranged as OAPs. There is clear evidence, however, that OAPs contain different AQP4 isoforms, mainly M1 and M23, which transport water in different capacities (Silberstein and others 2004). All these data have been reviewed recently (Wolburg and others 2011); therefore, in this review we use OAP descriptions only as evidence for the occurrence of AQP4. The formation of higher order complexes by AQP4 has recently gained attention by the use of intriguing molecular techniques that has been taken as additional evidence for OAPs (Crane and others 2011b; Crane and others 2008).

In the brain, AQP4 is located in the membranes of glial cells, more specifically on cells of the astroglial family (Nicchia and others 2010; Rash 2010). AQP4 in the brain is believed to play a role in maintaining ionic homeostasis, and involvement of these channels in neu-rological diseases is also well documented. The expres-sion pattern of AQP4 in the brain changes during phylogeny and ontogeny, which has consequences for CNS functions discussed below. Outside the nervous system, AQP4 is located in many epithelial structures involved in ion transport and secretion, for example, glandular tissues and the kidney, and in skeletal and smooth muscle cells. To better understand the principal rules how cellular polarity may be connected to physio-logical tasks, we will first briefly outline the localization

and functional aspects of AQP4 in non-neuronal tissue and then compare these with the role of AQP4 on glial cells in the mammalian central nervous system. Finally, we will consider AQP4 and astroglial structures in non-mammalian vertebrates to arrive at a hypothetical sce-nario on the evolution of astroglial function in vertebrates with implications for the ability of neurons to regenerate.

AQP4 Occurs in the Basolateral Membrane Domain of Epithelial Cells

In the respiratory system, AQP4 has been localized to the olfactory mucosa and to the cells of Bowman glands in the underlying lamina propria of the rat (Figs. 1 and 2A) (Ablimit and others 2008; Wolburg and others 2008b). In the following airways, the basolateral membrane domains of columnar cells of the trachea and of bronchus surface epithelial cells were also positive for AQP4 (Nielsen and others 1997). Alveolar cells are also believed to express AQP4 at least in some species (Kreda and others 2001; Verkman 2007; Wolburg and others 2011). In the urinary tract, AQP4 is expressed in the basolateral membrane domain of principal cells in the kidney collecting duct, along with AQP2 in the apical membrane of these cells (King and others 2004) (Fig. 2B). In parietal cells of the

Figure 1. Localization of tight junctions and the aquaporin-4 water channel in a typical epithelium. (A) Supporting cells in the olfactory mucosa and cells in the underlying Bowman’s glands in the nasal cavity of the rat show immunoreactivity for aquaporin-4 (red) in the basolateral membrane domain, and for the tight junction associated protein ZO-1 (green) below the surface, separating the apical from the lateral membrane domain. In (B) and (C) electron micrographs of freeze-fracture replicas demonstrate tight junction strands from the apical cell region (B) and orthogonal arrays of particles (arrows, C) at the basolateral membrane domain. (B) and (C) are modified from Wolburg and others (2008b).



Mack and Wolburg 197

stomach, presence of AQP4 was reported (Fujita and oth-ers 1999), clearly showing its basal localization (Fig. 2C). For human gastric cells in culture, AQP4 internal-ization and recycling stimulated by histamine has been suggested (Carmosino and others 2007). This regulation might be necessary to balance water uptake with apical HCl secretion as suggested by Fujita and others (1999), rather than AQP4 to be involved in secretion of water in parietal cells. In other regions of the digestive tract, cells in the crypts of the jejunum and ileum expressed AQP4 in their basolateral membrane domains (Koyama and others 1999; Ma and Verkman 1999).

AQP4 expression has also been reported for some glan-dular tissues, such as lacrimal glands (Ishida and others 1997) and salivary glands (Delporte and Steinfeld 2006).

All these expression patterns in epithelial cells share the characteristic of expressing AQP4 in the basal or

basolateral membrane domain (Fig. 2A–C). As far as we can determine, in all these cases, a junctional complex, including tight junctions just below the apical cell sur-face, was present on these epithelial tissues. This pre-sumably serves the function that epithelial cells involved in ion and water transport across the epithelium need to prevent paracellular backflow of the altered extracellular solution. Other aquaporins have been reported to be localized in the apical membrane domains and basolat-eral membranes depending on cell type or location of the cell type along the epithelium. For example, epithelial cells of the upper airway ducts express AQP3 in the basolateral membrane whereas in the bronchiolus epithe-lium where it is the only occurring AQP, it is expressed apically as well (Kreda and others 2001). However, AQP4 has never been reported to be present in the apical membrane domain.

Figure 2. Schematic diagrams depicting the localization of aquaporin-4 in various epithelia (A–C), striated muscle fibers (D), and sensory structures (E–G). Aquaporin-4 expressing cells are shown in green, and other cells are shown in yellow. In all epithelia, aquaporin-4 water channels are located in the basolateral membrane domain and never at the apical cell surface. Examples for expressing cells are drawn from the respiratory epithelium (A), parietal cells of the stomach (B), and from principal cells of the kidney collecting duct (C). Supporting cells in the olfactory mucosa (E), Müller glial cells in the retina (F), and various cells in the organ of Corti (G) express aquaporin-4 in a polarized distribution as well. In none of these organs do sensory cells express aquaporin-4. See text for details.




Muscle Cells and AQP4

AQP4 expression is by no means restricted to ectodermal-derived or epithelial structures. Skeletal muscle fibers also express AQP4, which is lost in various dystrophic conditions (Crosbie and others 2002); for a short recent review, see Wakayama (2010). Expressed predominantly in fast twitch fibers, AQP4 is thought to enable muscle fibers to cope with the rapid volume changes occurring during contraction. Moreover, it might be involved in the regulation of osmolarity during high muscle activity (Fig. 2D). As will be discussed below, the heparansulfate proteoglycan agrin was detected as a molecule respon-sible for the aggregation of the acetylcholine receptor in the motor endplate of the muscle. More recently, agrin was shown to be involved in the aggregation of AQP4 to form OAPs in astrocytes (Fallier-Becker and others 2011). However, the clustering activity of agrin in mus-cle cells for the acetylcholine receptor and AQP4 might involve different scaffolding co-proteins of the dystro-phin–dystroglycan complex. This issue and a possible relationship of the clustering mechanisms have never been addressed.

AQP4 in Supporting Cells of Sensory StructuresOlfactory receptor cells lie embedded in the olfactory mucosa, which is part of the airway passage epithelium described above. The supporting cells are unequivocally positive for AQP4 on their basolateral membranes, but the olfactory receptor cells and their axons appear to be negative (Fig. 2E) (Ablimit and others 2006; Wolburg and others 2008b). An exception has been reported for the vomeronasal organ of the rat: Here, besides support-ing cells, the sensory cells express AQP4 on the lateral and basal membranes (Ablimit and others 2008). The functional implication of this difference to receptor cells in olfactory mucosa is not clear. There is no convincing evidence for the expression of AQP4 on any other sen-sory cell or neuron.

In the eye, AQP4 was detected in two ocular tissues, the ciliary body and the retina by PCR analysis (Patil and oth-ers 1997). By immunocytochemistry, localization was demonstrated in the non-pigmented cells of the ciliary epi-thelium and with a much stronger signal in the processes of Müller cells and astrocytes in the retina (Hamann and oth-ers 1998). Although the weak staining in the ciliary epithe-lium had been described by these authors to be localized to the basolateral and apical membranes, the issue has been clarified in a more rigorous study by Yamaguchi and others (2006): They showed AQP4 expression clearly restricted to the basolateral membrane. The expression of AQP by Müller cells (Fig. 2F), members of the astroglial family, will be discussed in the next section.

In the inner ear, AQP4 expression has been shown for supporting cells in the organ of Corti (Takumi and others 1998). Recently, these results have been substantiated in more detail showing that AQP4 is localized in the support-ing cells of the inner and outer sulcus, Hensen’s cells, and Claudius cells (Hirt and others 2011). Interestingly, this study could differentiate between a basolateral localiza-tion in some cell types (e.g., Hensen’s cells) and an exclusively basal expression in others (e.g., Claudius cells) not correlating with OAP formation (Fig. 2G).

Aquaporins in the gustatory system have been reported to be present in taste buds of the rat, more specifically, AQP1, AQP2, and AQP5 are expressed in taste cells, pos-sibly involved in detection of osmotic and pH changes (Watson and others 2007). There have been no reports so far on the presence of AQP4 in taste buds.

Taken together, the expression of AQP4 in sensory structures (Fig. 2E–G) follows largely the pattern of a strictly basolateral distribution as found in epithelial cells. It is with the noted exception restricted to support-ing or glial cells.

Polarized AQP4 Distribution in Brain Glial CellsAQP4 is the main water channel of the brain expressed exclusively in cells of the astroglial family which includes ependymal cells, retinal Müller cells, and cerebellar Bergmann glial cells (Jung and others 1994; Nagelhus and others 2004) (for a recent review, see Pasantes-Morales and Cruz-Rangel 2010). OAPs have been detected on astroglial membranes more than 30 years ago (Dermietzel 1974; Rash and others 1974) and their molecular constitu-ents have been established as AQP4 on astroglial mem-branes (Rash and others 1998). AQP4 is localized on astrocytic membranes in a highly polarized manner: The membrane domains facing blood vessels and the pial brain surface show high densities of AQP4, dropping off sharply in membranes not directly apposed to the basal lamina between endothelial cells and the astrocytic end-feet (Wolburg and others 2011). Here, AQP4 co-localizes with the potassium channel Kir4.1, which is thought to siphon off excess potassium with water; see review by Rash (2010). This is crucial for neuronal signaling since astroglial cells remove potassium to keep the homeostasis of extracellular fluids. The presence of AQP4 on mem-branes of Müller cells in a polarized distribution (Nagelhus and others 1998) is not surprising considering that the retina derived from the diencephalon is part of the CNS and is similar to AQP4 expression of astrocytes. The result corresponds well with previously described OAPs on Müller cells (Raviola 1977). Like in astrocytes, the density of OAPs and thus AQP4 is especially high on perivascular Müller cell processes (Fig. 2F). In avascular retinas (e.g., guinea pig and rabbit), however, it is high only




on membranes facing the vitreous (Gotow and Hashimoto 1989; Wolburg and Berg 1988). This vitreal surface is phylogenetically and ontogenetically homologous to the pial brain surface and corresponds to the basal side of the neuroepithelium (see below). The retina and its constitu-tive glial element, the Müller cells have also served as a model where the concepts of spatial buffering and the involvements of water and potassium channels in healthy and disturbed states have been developed (Eberhardt and others 2011; Goodyear and others 2010; Kofuji and

Newman 2004; Nagelhus and others 1999; Reichenbach and Bringmann 2010).

In our context, exploring the occurrence and functional implication of AQP4 expression together with or without tight junctions, two observations are of special interest. (a) During development, immunoreactivity to AQP4 emerges at a stage when the astroglial precursor cells are running radially through the brain tissue from the ventricular to the pial surface, but AQP4 distribution is not yet polarized (Fig. 3B, data in preparation). (b) Cells lining the ventricle

Figure 3. Expression of aquaporin-4 water channels in astroglial cells in the optic tectum of the zebrafish (A), in the developing mouse cortex at E18 (B), and adult mouse cortex (C-E). In both, fish brain and developing mouse brain, glial cells show immunoreactivity for aquaporin-4 along the radial extent of the entire cell without a recognizable polarized distribution. In contrast, immunoreactivity in the adult mammalian brain is almost completely restricted to perivascular and subpial astrocytic endfeet and ependymal cells (see Figs. 4 and 5). In (B) and (C) the sections were also stained for the tight-junction adaptor protein ZO-1 (green) showing positive staining in blood vessels and meninges. (D) and (E) show freeze fracture replicas of a brain microcapillary. They are formed by endothelial cells (Cap) interconnected by tight junctions (not visible) and surrounded by astrocytic endfeet (AEF in D). These endfeet are extremely crowded with orthogonal arrays of particles where the glial cells contact the subendothelial basal lamina. Histological preparations for figures (B) and (C) were provided by J.P. Vollmer and K. Wolburg-Buchholz, respectively.




(ependymal cells) and overlying neuronal tissue express AQP4 (Jung and others 1994) and do not form a tight bar-rier (Wolburg and others 2009b); in contrast, ventricle-lining cells covering the blood vessels forming the choroid plexus (by definition homologous to ependymoglial cells) form tight junctions (Mack and others 1987; Wolburg and Paulus 2010) and express AQP1 (Nielsen and others 1993) but not AQP4 (Fig. 5). Thus, where glia-related cells (cho-roid plexus epithelial cells) form a barrier (the blood–cerebrospinal fluid barrier), there is a mutual exclusiveness of tight junctions and AQP4.

AQP4 expression is strongly influenced by the sur-rounding tissue or the extracellular environment. Recently, evidence has accumulated that extracellular matrix compo-nents such as agrin, the dystrophin–dystroglycan complex, and laminin are involved in the polarization of AQP4 expression in astrocytes (Fallier-Becker and others 2011; Noël and others 2009; Noell and others 2009; Noell and others 2011). The role of extracellular matrix molecules in targeting AQP4 to membrane domains is not restricted to astrocytes but could be observed in kidney derived cells in culture (Tham and Moukhles 2011). Dystroglycan is also involved in forming the assemblies known as OAPs (Crane and others 2011a; Noell and others 2011; Rossi and others

2011). Interestingly, the way how AQP4 channels interact to form higher order complexes such as OAPs determines the binding affinity to antibodies. Anti-AQP4 antibodies are known to cause the autoimmune disease neuromyelitis optica (Crane and others 2011a; Noell and others 2011; Rossi and others 2011). The antibody/AQP4 binding affin-ity might in turn be influenced by the expression ratio of AQP4 isoforms (Hinson and others 2012). In addition, evi-dence suggests that AQP4 molecules in astrocytes form complexes with another membrane channel, the transient receptor potential vanilloid 4 (Benfenati and others 2011). This channel responds to mechanical stress with Ca++ influx, and together with AQP4 might function as an osmo-sensor for volume control, as the authors suggest.

Summarizing AQP4 expression we can state that this water channel plays a role in at least three different sce-narios: First, in an epithelial setting, AQP4 provides fast water transport in the basolateral membrane domain to facilitate secretion of water and solutes; second, in mus-cle cells, AQP4 appears to support the cells to cope with metabolic and volume challenges; and third, on astro-cytes, in the brain it facilitates the exchange of water along with potassium ions to meticulously maintain homeostasis for neuronal functioning.

Figure 4. Schematic diagram illustrating the topology of astroglial cells, expression of aquaporin-4, and formation of tight junctions in the brain of teleost fish (left), and the mammalian brain (right). In the fish brain, many astroglial cells run radially from the ventricular to the brain surface. They form tight junctions at the ventricular surface and express aquaporin-4 without any particular preference over the cell surface. In contrast, in astrocytes of the mammalian brain, aquaporin-4 channels are distributed unevenly: High densities are located at perivascular and subpial processes. In addition, ependymal cells lining the ventricular surface display aquaporin-4 on the basolateral membrane. However, where these cells face blood vessels as epithelial cells in the choroid plexus they are connected by tight junctions and lack aquaporin-4.




Epithelial Nature of Astroglial Cells

Neuroectoderm starts out as an epithelial structure where cells span the entire width of the epithelium with clearly defined apical and basal poles and form tight junctions (Lowery and Sive 2009; Zhang and others 2010). Thus, according to the infolding of the neural tube, the ven-tricular surface represents the apical domain, and the future pial surface of the brain the basal side of the neu-roepithelium. Going through a stage of radial glia, mam-malian astrocytes form contacts to blood vessels contributing to the blood-brain barrier, and/or to the pial surface. The epithelial nature is evident by the presence of cilia as an apical differentiation on ventricle-lining cells, organizing also their planar polarity (Mirzadeh and others 2010). Despite their polarized organization no api-cal or basal side can be defined on astrocytes. Exceptions are not only ependymal and choroid plexus cells but also glial cells at locations where the radial phenotype is maintained like in the Müller cells of the retina. In fish, radial glia is the predominant astroglia type in the adult CNS (see below). In the case of the epithelium in the early neural tube, tight junctions are indeed formed during

neural tube formation but are lost later in mammalian development (Aaku-Saraste and others 1996).

As brain tissue thickens during development, and glial cells are challenged by increasing demands to maintain homeostasis, contact to the ventricular and pial surfaces is lost and radial glial cells differentiate as astrocytes sur-rounding blood vessels with their endfeet. Increasing vas-cularization in brain development requires improved transport and barrier functions at the blood-brain inter-face. The barrier for blood-borne substances is primarily formed by endothelial cells connected by tight junctions. This has led to the research concept of distinguishing between vascular and neuronal compartments in the brain (Wolburg and others 2009a) (Fig. 4). Thus, astroglial cells maintain a highly polarized structure but pass the actual barrier properties in the form of tight junctions over to endothelial cells or the specialized choroid plexus cells.

Physiological Aspects: The Direction of Water Flow in Ependymal and Epithelial-Type Cells Expressing AQP4

In general, aquaporins are open for water to pass through without a directional preference. Hence, water flow is determined by the osmotic gradient and hydrostatic pres-sure, which in turn depend on a cell’s composition of ion pumps, exchangers, and channels. In glandular cells, like in lacrimal and Bowman’s glands and parietal cells, apical secretion is thought to be supported by water inflow through basolaterally located AQP4. In kidney collecting duct cells, water uptake is performed apically by vasopres-sin controlled AQP2, and therefore water flows out through basal AQP4 channels. In astrocytes, the general water flow at the perivascular and subpial endfeet is believed to be outward along with K+ passing through Kir4.1 potassium channels. This contributes to the removal of the relatively high [K+] in synaptic areas and at the nodes of Ranvier. It has been proposed that water enters astrocytes in the pre-synaptic regions through the few water channels found there, or other pathways (Rash 2010) and is then directed to the perivascular or subpial processes where it leaves the cell via the densely packed AQP4 channels.

As pointed out above, when AQP4 is expressed in epi-thelial cells it is always localized in the basolateral mem-brane. Although basolateral and apical domains are not defined for differentiated astrocytes, their highly polarized AQP4 expression results in a directed water flow. This water outflow is disturbed in brain diseases like tumors leading to edemas (Wolburg and others 2008a) indicating the loss of polarity. Recently, Illarionova and others (2010) provided evidence for a close interaction of Na+/K+ ATPase and AQP4 in the membranes of astrocytes. The authors suggest that this interaction has functional implication in

Figure 5. Transition zone between ependymal cells lining the lateral ventricle and the choroid plexus epithelial cells in the mouse brain. Ependymal cells express aquaporin-4 (green) basolaterally. There is no barrier junction separating cerebrospinal fluid from the brain interstitial space. In contrast, plexus epithelial cells express aquaporin-1 apically (red) and form tight junctions. Interestingly, there are some cells in the transition zone that express both types of aquaporins (arrows). In the brain parenchyma, astrocytic endfeet surrounding blood vessels are also positive for aquaporin-4.




removing excess K+ from perisynaptic regions. However, as mentioned above, the bulk of AQP4 in astrocytes is located in the perivascular and subpial regions and a direct co-localization with ATPase as it occurs in other tissues, has not been shown. Nevertheless, the possibility of the interaction of Na+/K+ ATPase and AQP4 to create an osmotic (and/or concentration) gradient involved in K+ removal from the synaptic region is intriguing.

Apical localization of Na+/K+ ATPase in zebrafish radial glial cells bordering the ventricle is thought to pro-vide a gradient to induce cerebrospinal fluid flow during development (Lowery and Sive 2005). Na+/K+ ATPase has also been localized to the apical brush border mem-brane of choroid plexus cells, which produce the cerebro-spinal fluid in the adult mammalian brain (Brown and others 2004). Interestingly, this is in contrast to the Na+/K+ ATPase localization in the basolateral membrane domain of most other epithelia (e.g., kidney tubule cells, salivary gland cells). In choroid plexus epithelial cells, the apical outward pumping of sodium has the effect of subsequent water flow through the apically located AQP1 water chan-nels (Brown and others 2004). In addition, the ATPase also removes potassium from cerebrospinal fluid. Whether this might contribute to brain homeostasis which requires potassium to be removed from the perineuronal extracel-lular space remains to be shown.

Water Flow and Barriers: The Relationship of Tight Junctions and AQP4

Epithelial cells with basolateral AQP4 expression display apical junctional complexes, limiting extracellular transepithelial water flow (e.g., Wolburg and others 2008b). Is this also true for astroglial cells and their epen-dymal derivatives? Tight junctions of the choroid plexus epithelium represent the molecular/morphological corre-late of the blood-ventricular barrier and prevent the back-flow of solutes from the ventricles. In contrast, no such barrier exists between the ventricle and the neuronal com-partment on the level of (non-plexus) ependymal cells, which express AQP4 basolaterally. However, tight-junction bearing choroid plexus epithelial cells express AQP1 apically and no AQP4 (Wolburg and Paulus 2010). The hypothesis of mutual exclusiveness of tight junctions and (AQP4-containing) OAPs on cells of the astroglial family has been stated before the discovery of aquaporins (Mack and others 1987). This exclusiveness was supported by morphological freeze-fracture data of olfactory ensheathing glia, fish optic nerve, lizard spinal cord, and circumventricular organs (Mack and Wolburg 1986; Mack and Wolburg 2006; Neuhaus and Wolburg 1985). Glial cells in these regions form tight junctions and do not

express AQP4 containing OAPs. However, it should be noted that these observations are restricted to the neuronal compartment. In epithelial structures expressing AQP4 basolaterally, an apical junctional complex, including tight junctions, has been well described (see above). Regarding other junctions in the context of aquaporins, one study describes an interaction between connexin 43 and AQP4 (Nicchia and others 2005): Knockdown of AQP4 in pri-mary mouse astrocytes cultures evoked a decrease of con-nexin 43. The authors discuss the parallel regulation of AQP4 and connexin 43 as being important for the facilita-tion of the glial buffering capacity under these conditions. A corresponding study on tight-junction protein expres-sion in AQP4-deficient cells has not been done yet.

Evolutionary AspectsAstroglial cells are present in the brains of all vertebrates. Except microglial cells, all neurons and glial cells in the CNS are derived from the neural tube. In fish brains, astroglial cells retain long processes and run—depending on brain structure—radially with contact to the pial and ventricular surface (Kalman 1998). In contrast to mam-mals, desmosomes and tight junctions have been found on fish astroglial cells (for review, see Lara and others 1995, Fig. 4). Studies on agnathans and elasmobranchs revealed specialized junctions on astroglial processes surrounding blood vessels (Bundgaard and Cserr 1981). Therefore it was proposed that “all vertebrates started out with a glial blood-brain barrier 4-500 million years ago” (Bundgaard and Abbott 2008). Recently, junctional complexes were found on ventricular and pial processes of radial glial cells in the zebrafish brain (Grupp and others 2010). Therefore, it appears that in fish the ventricular environment is sepa-rated from the neuronal compartment. These zebrafish radial glial cells were immunopositive for AQP4; how-ever, occurring not as polarized but spread over the radial extent of the cells. Based on the observation that ventricu-lar space and therefore CSF develops before the choroid plexus has been formed, it has been suggested that early ependymal/radial glial cells have secretory function (Lowery and Sive 2009). Whether this is maintained in the adult fish brain is not known.

In this context, it is noteworthy that brain growth con-tinues in most fish into adulthood from distinct prolifera-tion zones (Grupp and others 2010; Mack and Fernald 1995; Wullimann and Puelles 1999). These proliferation zones add new tissue to the CNS that includes the gen-eration of neurons and glia. At least embryonic CSF has been suggested to play a role in proliferation and neuro-genesis (Lowery and Sive 2009). The highly polarized distribution of AQP4 and Kir4.1 at the endfeet of mam-malian astrocytes indicates an optimization toward ionic and osmotic homeostasis, facilitating improved neuronal




performance. By definition, radial glial cells are ependy-mal cells and give rise to the cuboidal ependymal cells found in mammals. The expression of AQP4 on mam-malian ependymal cells indicates their involvement in water transport, but they do not form a barrier between the neuronal and ventricular environment due to the loss of tight junctions during ontogeny and phylogeny. In contrast, radial glial cells (which includes cells in the proliferative zones) in adult fish and developing mam-malian brain have access to the ventricles and form api-cal junctions. Improved ionic homeostasis in mammals might have occurred on the expense of restraining growth and neurogenesis.

Correlation of AQP4 Expression and RegenerationThe ontogenetic and phylogenetic aspects outlined above gave rise to the observation that glial cells form-ing tight junctions, and expressing no or unpolarized AQP4 are found in regenerative neural structures. More specifically, this becomes clear in the following paradigms:

1. The fish optic nerve, well known for its regen-erative capacity, forms tunnel-like structures after injury. These tunnel-like structures con-sisted of tight junction–connected astrocytes (Wolburg and others 1983). In addition, the continuously growing nerve fibers to the optic tectum were wrapped by astrocytes expressing the tight junction protein claudin-1 (Mack and Wolburg 2006). AQP4 containing OAPs were not detected.

2. In the regenerative caudal spinal cord of the lizard Anolis, astrocytes are connected by tight junctions and do not arrange AQP4 as OAPs, whereas in the non-regenerative thoracic spinal cord they display polarized AQP4-containing OAPs (Neuhaus and Wolburg 1985).

3. In a study on the olfactory system, we hypoth-esized that glial tight junctions might isolate microcompartments that are conducive for axonal growth (Fig. 6) from areas that are opti-mized for ionic homeostasis (Wolburg and oth-ers 2008b). The fila olfactoria are surrounded by perineural cells interconnected by claudin-1 positive tight junctions. The olfactory axons are bundled by the olfactory ensheathing cells, which are interconnected by claudin-1 nega-tive, but claudin-5 positive tight junctions. However, both types of tight junctions at this location were not so tight to hinder completely the diffusion of small amounts of injected lanthanum into the interaxonal space. The authors discussed this special situation with the assumption that the olfactory axons were protected from the mass of blood-borne sub-stances among which neurotoxic compounds were likely present, yet exposed to components favorable for growing axons. In this scenario, fast and polarized water movement by AQP4 might not be necessary or even exacerbating or hindering growth processes.

In addition, polarized AQP4 expression on astrocytes occurs at a time during development when the capability of axonal regeneration in the CNS decreases. However,

Figure 6. Schematic diagrams of the glial arrangement in the mammalian olfactory nerve (left) and brain parenchyma (right). The olfactory ensheathing (glial) cells (OECs) are interconnected by tight junctions and surround axons presumably providing a growth-promoting microenvironment. In contrast, astroglial cells in the mammalian brain are not interconnected by tight junctions, thus the neuropil is not separated from axons. Instead, astrocytes express aquaporin-4 in a polarized manner providing for optimized ionic homeostasis. For more details, see text.




tight junctions on radial glia are lost much earlier during development (Aaku-Saraste and others 1997).

A relationship of AQP4 to regeneration is supported by the recent report that this water channel is down-regulated after rat optic nerve crush (Zickler and others 2010). Indeed, and highly interesting for our hypothesis linking AQP4 and regeneration, are experiments on the AQP4-knockout mouse. These animals have been described to have a benefit for regeneration capacity after spinal cord compression injury inducing cytotoxic edema (Saadoun and others 2008). However, after contu-sion injury inducing vasogenic edema, the presence of AQP4 was beneficial compared with AQP4-lacking ani-mals, presumably protecting neurons from cell death (Kimura and others 2010). This is consistent with our view outlined above that highly polarized expression of AQP4 in the mammalian CNS improves the neuronal environment. In the case of the cytotoxic edema, Saadoun and others (2008) argue that AQP4 provides a major route for excess water entry into the injured spinal cord, which in turn may cause spinal cord swelling and ele-vated spinal cord pressure. A transient AQP4 inhibition or down-regulation could therefore be a novel approach for early neuroprotective therapy after spinal cord injury. So far, it is not known whether the astrocytes in the compression-injured AQP4-deficient system have developed interglial tight junctions. However, besides the water transport function, it is also conceivable that AQP4 could serve other functions in a non-regenerative environment. For example, cell adhesion and cell migra-tion has been suggested by some studies (Engel and oth-ers 2008; Hiroaki and others 2006) yet disputed by others (Zhang and Verkman 2008).

ConclusionsWhen expressed in epithelial cells, AQP4 is located in the basolateral membrane domain with an apical junc-tional complex. Astrocytes derived from neuroectoderm are modified from their “epithelial” role with apical junc-tional properties and basolateral facilitated water flow to a specialized cell with homeostasis function lacking a direct junctional barrier. This can be observed in stages of phylogeny and ontogeny when cells lining the ventri-cle transform from a radial phenotype to cuboidal epen-dymal cells, to astrocytes with highly polarized AQP4 expression (Fig. 3), or maintaining epithelial properties in the differentiation to choroid plexus cells. This sug-gests a shift in the mechanism to achieve homeostasis in the mammalian brain by a high level of AQP4/OAP polarization and a loss of tight junctions, and this in turn might have been the starting point to lose regenerative capacity in the CNS.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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