In vertebrates, the family of tenascins comprises the four members tenascin-C, -R, -W and -X (Chiquet-Ehrismann and Tucker, 2011; Chiquet-Ehrismann et al., 2014). Expression of tenascin-R (Tnr) is restricted to the nervous system, whereas tenascin-C (Tnc) can also be found in non-nervous tissue. Due to the fact that little, if anything, has been reported about the role of tenascin-W and -X in the diseased visual system, this review article mainly focuses on the expression and functional importance of Tnc and Tnr in retinal and optic nerve degeneration and various eye diseases.

Both tenascin molecules exhibit a modular structure (Nies et al., 1991; Siri et al., 1991; Jones F. S. and Jones, 2000; Jones P. L. and Jones, 2000; Joester and Faissner, 2001; Midwood and Orend, 2009). Tnc is an oligomeric protein, which consists of six monomers that are connected via a tenascin assembly (TA) domain at the amino-terminal region (Figure 1A). This constitution is also called hexabrachion. In human, each TNC monomer consists of a TA domain, followed by a cysteine-rich domain, 14.5 epidermal-growth factor (EGF)-like domains, eight fibronectin (FN)-type III domains and a fibrinogen (FG)-like carboxy-terminal part. Additional FN-type III domains, termed A1, A2, A3, A4, B, AD2, AD1, C and D, can be inserted between domain 5 and 6 (Spring et al., 1989; Nies et al., 1991; Dörries and Schachner, 1994; Joester and Faissner, 1999, 2001; Tucker et al., 2006). Via alternative TNC mRNA splicing, and based on a binary combinatorial potential, the generation of up to 512 isoforms in humans is feasible (Joester and Faissner, 1999, 2001; Theocharidis et al., 2014; Midwood et al., 2016; Faissner et al., 2017). One interesting feature of Tnc is that it exhibits both adhesive and anti-adhesive properties (Faissner and Kruse, 1990; Chiquet-Ehrismann et al., 1991; Faissner, 1997). For instance, the FN-type III region exhibits pro-adhesive characteristics, whereas the EGF-like domains show anti-adhesive properties (Spring et al., 1989; Ajemian et al., 1994; Gotz et al., 1996). The latter are also associated with proliferation, growth cone repulsion and migration (Joester and Faissner, 2001; Swindle et al., 2001; Loers and Schachner, 2007). Human TNR exhibits a similar modular structure, but it is composed of three monomers (Figure 1B; Schachner et al., 1994). Each monomer consists of an amino-terminal TA domain, a cysteine-rich domain, 4.5 EGF-like repeats, eight or nine FN-type III domains and a FG carboxy-terminal part.

As part of the eye (Figure 2A), the retina and the optic nerve develop from neuroectodermal tissue. During retinogenesis, seven main cell types, namely retinal ganglion cells (RGCs), amacrine, bipolar, horizontal, Müller glia as well as cone and rod photoreceptor cells, arise from multipotent retinal progenitor cells in highly conserved and overlapping waves (Cepko et al., 1996; Dyer and Cepko, 2001; Marquardt, 2003; Agathocleous and Harris, 2009; Heavner and Pevny, 2012). Until adulthood, following a maturation and synaptic fine-tuning period, retinal cell nuclei are assigned to specific nuclear layers, while their synaptic processes are arranged in plexiform and nerve fiber layers (Figure 2B).

Indeed, the retina is an excellent model system to study developmental aspects such as proliferation and differentiation, but also axonal growth and guidance as well as pathfinding (McLaughlin et al., 2003; Oster et al., 2004). Nasal and temporal projections from the retina are transmitted via RGC axons, which form the optic nerve. RGC axons from both eyes converge in the optic chiasm at the base of the hypothalamus and segregate into ipsi- and contralaterally projecting fibers (Petros et al., 2008; Erskine and Herrera, 2014). Via the optic tract, axons project in a highly topographic manner into subcortical and cortical areas to transfer the visual information.

Intrinsic and extrinsic factors, which comprises transcription factors, growth factors and a variety of ECM components, including tenascins, influence retinogenesis and the growth of optic nerve fibers (Thanos and Mey, 2001; Hatakeyama and Kageyama, 2004; Harada et al., 2007; Agathocleous and Harris, 2009; Xiang, 2013; Reinhard et al., 2015).

In the developing retina, Tnc becomes detectable within the inner neuroblastic layer at embryonic day 13 (Klausmeyer et al., 2007). In the adult retina, it is synthesized by different neuronal subtypes, including horizontal, amacrine and displaced amacrine cells and is prominently enriched in the outer and inner plexiform as well as in the nerve fiber layer (D’Alessandri et al., 1995; Sánchez-López et al., 2004; Figure 2C). As shown by Siddiqui et al. (2009), cultivated postnatal Müller glia cells also express large Tnc isoforms. In the optic nerve, astrocytes secrete huge amounts of the Tnc protein (Bartsch et al., 1995; D’Alessandri et al., 1995; Garwood et al., 2004; Reinhard et al., 2015).

Tnr, also known as janusin/J1-160/180 in rodents or restrictin in the chicken, is initially expressed upon postnatal stages in the developing retina and optic nerve (Ffrench-Constant et al., 1988; Bartsch et al., 1993; Wintergerst et al., 1993; Joester and Faissner, 2001). Later, Tnr expression peaks until the third postnatal week and then decreases again. In the adult retina, horizontal cells are the main cellular source of Tnr (Figure 2C). Due to the proximity of Tnr-expressing cells, large amounts of protein are found in the outer plexiform layer. Nevertheless, the inner plexiform and nerve fiber layer also show detectable levels of the Tnr protein, suggesting low expression by other retinal cell types or intraretinal protein transport. In the optic nerve, it is highly expressed by oligodendrocytes and associated with myelinated fibers and nodes of Ranvier with ongoing age until adulthood. In contrast, Tnr is absent from the unmyelinated proximal, retina-near part of the optic nerve.

Glaucoma is one of the leading causes of visual impairment and irreversible blindness worldwide. It is a neurodegenerative disease characterized by morphological changes of the optic nerve head and retinal nerve fiber layer as well as progressive RGCs loss (EGS, 2017). In 2010, approximately 4.2 million people were visually impaired due to glaucoma (Bourne et al., 2016). This number will likely rise to about 11.2 million people by 2020 (Quigley and Broman, 2006). Among others, age, genetic predisposition and intraocular pressure (IOP) elevation are considered the most important risk factors for glaucoma. However, its pathophysiology is still poorly understood.

Various studies indicate that remodeling of Tnc is strongly associated with high-pressure glaucoma (Table 1). Pena et al. (1999) recognized that enhanced Tnc expression is associated with reactive astrocytes in the human optic nerve head of primary open-angle glaucoma (POAG) patients. Although the precise function of Tnc in glaucoma disease is still unknown, it was assumed that it might act as barrier molecule, which locally restricts detrimental humoral and blood-derived factors, to protect RGC axons. Along these lines, Johnson et al. (2007) described a prominent Tnc upregulation in the pressure-injured optic nerve head of a rat ocular hypertension glaucoma model. Additionally, Tnc might be involved in reactivation of astrocytes, which play a crucial role in glaucomatous optic nerve fibrosis (Schneider and Fuchshofer, 2016).

IOP rises due to impaired aqueous humor outflow via the trabecular pathway in the iridocorneal angle (Abu-Hassan et al., 2014; Dautriche et al., 2014). In this regard, it is interesting to note that Tnc is an extracellular component within the human juxta-canalicular tissue (JCT). In addition, Tnc was detected in trabecular meshwork (TM) cells (Ueda and Yue, 2003; Pattabiraman and Rao, 2010; Keller et al., 2013; Figure 2B). In the JCT, Tnc is predominantly localized in basement membranes underlying the inner wall of Schlemm’s canal (Figure 2C).

An abnormal accumulation of ECM constituents increases aqueous humor outflow resistance through the trabecular pathway (Gabelt and Kaufman, 2005). The functional importance of matricellular protein production and turnover to control outflow resistance in the TM has been reviewed (Wallace et al., 2014, 2015; Tamm et al., 2015). Several matricellular proteins, including the connective tissue growth factor, thrombospondin, Tnc and Tnx, appear to play a role in TM fibrosis. For instance, deficiency of the matrix glycoproteins thrombospondin 1 and SPARC (secreted protein acidic and rich in cysteine) has been shown to enhance outflow facility and lower IOP in mouse models of glaucoma (Wallace et al., 2015).

Keller et al. (2007) noted increased levels of Tnc in response to mechanical stretching of porcine TM cells in a perfusion culture model. Isoforms of Tnc identified in those TM cells included FN-type III 5-D-6, 5-6, A1-B as well as B-D-6. Interestingly, levels of Tnc FN-type III domain D transcripts were also elevated due to mechanical stretching of TM cells, indicating changes in alternative splicing that might affect TM cell-ECM interaction.

The effects of Tnc knockdown on TM outflow resistance were studied in more detail in anterior segment perfusion organ cultures (Keller et al., 2013). Here, Tnc was upregulated in response to IOP elevation. Nevertheless, the outflow rate was not altered by Tnc-silencing in anterior segments following IOP elevation. In addition, IOP was not altered in Tnc knock-out compared to control mice, indicating that Tnc does not directly contribute to the regulation of outflow resistance. However, Yang et al. (2016) described the effects of induction and inhibition of matrix cross-linking on remodeling of the aqueous humor outflow resistance by TM cells. In this study, genipin, a potent inducer of ECM crosslinking and inhibitor of aqueous humor outflow, reduced the levels of Tnc and other ECM components such as collagen I, elastin and the chondroitin sulfate proteoglycan (CSPG) versican. These findings indicate that changes in the ECM composition, crosslinking and turnover are highly dynamic and influence outflow resistance. Recently, the group around Kuehn showed a positive effect on outflow facility after transplantation of induced pluripotent stem cell-derived TM cells into a glaucoma model. Since the transplanted cells do not persist for long, it was theorized that the cells might alter TM conditions (Zhu et al., 2016, 2017). These alterations could also be related to changes in the ECM. The TM serves as an important target for the treatment of IOP elevation in glaucoma (Ferrer, 2006). In a future perspective, further knowledge of ECM-TM physiology is necessary to develop novel and powerful IOP lowering therapies.

Tenascins are also key regulators of the immune system and neuroinflammatory processes (Jakovcevski et al., 2013). A complex interplay and functional relationship between neural and immune cells in various autoimmune diseases, e.g., multiple sclerosis and neuropathies, are evident. Tnc was reported as one major ECM component, which modulates transforming growth factor β (TGFβ)/Smad signaling and myofibroblast generation during wound healing of the corneal stroma (Saika et al., 2016). Also in the TM, TGFβ increases outflow resistance via alteration of ECM homeostasis and cell contractility (Fuchshofer and Tamm, 2012; Prendes et al., 2013; Wang et al., 2017). In addition, Tnc was previously reported to influence the immune system through the toll-like receptor 4 (TLR4; Midwood et al., 2009). It promotes an inflammatory response via macrophage generation, activation of TLR4 and the secretion of proinflammatory cytokines after stimulation with lipopolysaccharide (Piccinini and Midwood, 2012; Piccinini et al., 2016). Indeed, Tnc deficiency protects mice from experimental autoimmune encephalomyelitis and plays a key role in pathogenesis of CNS autoimmunity (Momcilovic et al., 2017). Interestingly, various studies have shown that TLR4 gene polymorphisms are associated with an increased risk of glaucoma (Shibuya et al., 2008; Navarro-Partida et al., 2017a,b). This confirms that TLR4-mediated signaling is involved in this disease.

Several studies have also investigated the possible involvement of the immune system in glaucoma pathogenesis (Tezel and Wax, 2004; Tezel, 2009; Rieck, 2013; Ramirez et al., 2017). Recently, we have noticed Tnc dysregulation in an IOP-independent, experimental autoimmune glaucoma model (Reinehr et al., 2016b). In this glaucoma model, RGC loss, optic nerve damage, reactive gliosis as well as complement activation have been described (Joachim et al., 2013, 2014; Casola et al., 2015; Noristani et al., 2016; Reinehr et al., 2016a). Furthermore, upregulation of Tnc and the CSPG phosphacan, an interaction partner of Tnc, was found in the retina and optic nerve of the autoimmune glaucoma model (Reinehr et al., 2016b). Most interestingly, elevated Tnc levels were observed before RGC loss occurred in this model. Regarding this finding, Tnc might act as an early indicator of glaucomatous neurodegeneration, although the function of Tnc in IOP-independent glaucoma is not well understood yet.

Ischemia represents a common pathomechanism in several retinal diseases, like age-related macular degeneration (AMD), diabetic retinopathy, glaucoma and retinal vascular occlusion (Mizener et al., 1997; Coleman et al., 2013; Sim et al., 2013).

Several studies reported on a dysregulation of Tnc following cerebral, hepatic as well as myocardial ischemia (Lu et al., 2003; Taki et al., 2010, 2015; Kuriyama et al., 2011). We recently analyzed the regulation of ECM glycoproteins and proteoglycans in the retina and optic nerve of an ischemia/reperfusion rat model (Reinhard et al., 2017; Table 1). An interesting finding of this study includes the prominent upregulation of several CSPGs in the ischemic optic nerves. Furthermore, in the retina, elevated levels of the large Tnr isoform were found, while reduced levels of smaller Tnc isoforms were observed after ischemia/reperfusion. These findings support the idea of an isoform-dependent regulation of tenascins. In future studies, domain-specific Tnc antibodies (Brösicke et al., 2013; Reinhard et al., 2016) should be used to relate specific isoforms to distinct retinal cell types under pathological conditions.

In the CNS, tenascins represent main structural and functional constituents of synaptic sites (Dityatev et al., 2010; Kwok et al., 2011; Heikkinen et al., 2014; Dzyubenko et al., 2016; Song and Dityatev, 2017). Also in the retina, tenascins are highly associated with synaptic layers (Bartsch et al., 1993; D’Alessandri et al., 1995; Wahlin et al., 2008). We have previously shown a co-localization of Tnc and synaptophysin in the healthy retina (Reinhard et al., 2015). In sum, the dysregulation of tenascins after retinal ischemia might reflect the response or damage of retinal neurons or synaptic reorganization.

AMD is defined by a deterioration of the macula and represents a major cause of vision impairment worldwide (Jager et al., 2008; Ding et al., 2009; Lim et al., 2012). It is a multifactorial disease that affects primarily photoreceptor cells, retinal pigment epithelium (RPE), Bruch’s membrane as well as choriocapillaries (Bhutto and Lutty, 2012). Additionally, AMD is characterized by extracellular depositions between Bruch’s membrane and the RPE, termed drusen, which includes complement components, glycoproteins and lipids (Crabb, 2014; Fernandez-Godino et al., 2016). Choroidal neovascularization is the defining characteristic of wet AMD.

The tenascin family member Tnx was identified in AMD patients in a genome-wide association study (Cipriani et al., 2012). In a plasma protein screen to identify biomarker, Tnx was differentially expressed in AMD patients compared to the healthy controls (Kim et al., 2014).

Additionally, high levels of Tnc were observed in choroidal neovascular membranes from AMD patients (Nicolò et al., 2000; Fasler-Kan et al., 2005; Afshari et al., 2010; Kobayashi et al., 2016b; Table 1). Here, RPE cells restricted to scar areas exhibited a strong staining for Tnc. Tnc was also identified as a candidate to cause RPE adhesion failure in damaged and aged Bruch’s membrane. In this regard, Afshari et al. (2010) described that Tnc inhibits RPE attachment and migration. Interestingly, this inhibition can be overcome via integrin activation or expression of Tnc-binding integrin α9, which allows RPE cells to interact with the AMD-affected Bruch’s membrane (Afshari et al., 2010). Additionally, Tnc secretion by transdifferentiated RPE cells is considered to promote choroidal neovascular membrane formation via integrin αv in a paracrine manner (Kobayashi et al., 2016b). Here, Tnc was discussed as potential target for the inhibition of choroidal neovascular membrane formation in AMD.

Diabetic retinopathy is also highly associated with retinal vascular dysfunction. Tnc was found in intravitreal membranes of patients with traumatic and idiopathic proliferative vitreoretinopathy as well as in diabetic retinopathy (Hagedorn et al., 1993; Table 1). In light of these results, it was suggested that Tnc likely controls cellular adhesion and ECM formation under pathological conditions. Structural, morphological as well as biophysical changes of ocular vasculature basement membranes were reported to be accompanied by ECM remodeling (To et al., 2013). Here, a higher Tnc expression was detected in basement membranes of diabetic compared to non-diabetic human eyes. Additionally, Tnc was reported to be involved in inflammatory processes of diabetic retinopathy. Increased Tnc levels were found in retinal endothelia cells following tumor necrosis factor α and interleukin 1β stimulation (Palenski et al., 2013). Expression analysis in fibrovascular membranes from patients with proliferative diabetic retinopathy revealed an upregulation of Tnc (Ishikawa et al., 2015). Recently, Kobayashi et al. (2016a) showed that Tnc, secreted from vascular smooth muscle cells, promotes angiogenesis in fibrovascular membranes associated with diabetic retinopathy.