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Keywords:

  • decorin;
  • extracellular matrix;
  • neural development;
  • small leucine rich proteoglycan family;
  • Tsukushi

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Germ layer specification
  5. Organizer formation and neural induction
  6. Neural specification (neural crest specification)
  7. Neural precursor cell migration and differentiation
  8. Neural stem niches
  9. CNS injury response
  10. Functions in non-neural ocular/eye tissues
  11. Future direction
  12. Acknowledgments
  13. References

The small leucine-rich repeat proteoglycan (SLRPs) family of proteins currently consists of five classes, based on their structural composition and chromosomal location. As biologically active components of the extracellular matrix (ECM), SLRPs were known to bind to various collagens, having a role in regulating fibril assembly, organization and degradation. More recently, as a function of their diverse proteins cores and glycosaminoglycan side chains, SLRPs have been shown to be able to bind various cell surface receptors, growth factors, cytokines and other ECM components resulting in the ability to influence various cellular functions. Their involvement in several signaling pathways such as Wnt, transforming growth factor-β and epidermal growth factor receptor also highlights their role as matricellular proteins. SLRP family members are expressed during neural development and in adult neural tissues, including ocular tissues. This review focuses on describing SLRP family members involvement in neural development with a brief summary of their role in non-neural ocular tissues and in response to neural injury.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Germ layer specification
  5. Organizer formation and neural induction
  6. Neural specification (neural crest specification)
  7. Neural precursor cell migration and differentiation
  8. Neural stem niches
  9. CNS injury response
  10. Functions in non-neural ocular/eye tissues
  11. Future direction
  12. Acknowledgments
  13. References

A number of signaling pathways have been identified to govern development of the neural system. Such signaling pathways are largely triggered by secreted extracellular proteins such as Nodal, fibroblast growth factors (FGFs), Wnts and Shh. These secreted ligands bind their cell surface receptors and transmit the extracellular information into the cells. Finally, the cells perform their function based on the transmitted signals, the processing of which is largely handled in the nucleus. Many recent studies have elucidated that each developmental/cellular event is often regulated by a combination of multiple signaling pathways, and a significant number of extracellular proteins act as extracellular signaling co-ordinators. These proteins are known as matricellular proteins.

The small leucine rich proteoglycan (SLRP) family consists of 17 members of secreted proteins (Fig. 1). Structural analysis has shown that SLRPs consist of two main structural components, a conserved protein core and several different types and numbers of glycosaminoglycan (GAG) side chains, which form chondroitin (CS), keratan (KS), dermatan (DS), or heparan-sulfate (HS) (Iozzo et al. 1997; Hocking et al. 1998; Iozzo 1998). The core proteins contain a number of leucine-rich repeats (LRRs), which consist of the consensus sequence LXX-LXLXXNXL, where X is any amino-acid, L is leucine, isoleucine or valine, and N is asparagine, cysteine or threonine. These LRRs are usually flanked by sequences with four cysteine residues at the N-terminal and with two cysteine residues at the C-terminal parts of the proteins (Table 1). Based on the number of the LRRs as well as the spacing of the N-terminal cysteine residues and their chromosomal organization, these proteins have been subdivided into five classes (Fig. 1, Table 1) (Iozzo et al. 1999; Henry et al. 2001). For example, Decorin was first identified in 1986 as a small structural protein from collagen bound extracellular complex. Decorin has 12 LRRs and either a CS or DS sugar chain (Scott et al. 2004). Keratocan, which localizes in corneal extracellular matrix, has 12 repeats and KS sugar chain.

image

Figure 1. Phylogenetic tree and structure of the small leucine-rich repeat proteoglycan (SLRP) family. Phylogenetic analysis of the SLRP family and structural organization. (a) Dendrogram displaying the phylogeny and the five distinct classes of the growing SLRP protein family. Generated by multiple sequence alignment using ClustalW2 from the European Bioinformatics Institute (http://www.ebi.ac.uk/Tools/msa/clustalw2/); (b) structural organization of Decorin and Tsukushi: each circle represents a leucine rich repeat (LLR) with the number of residues written inside it, while the circles are shaded according to their length. The red leucine-rich repeat (LRR) in decorin named E-30 is the extended Ear repeat having 30 residues, while Tsukushi (TSK) has no such motif. Instead, the two last LRRs of Tsukushi (shaded green), represent a C-terminal cap motif, which is often found in other eukaryotic LRR proteins (Mcewan et al. 2006).

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Table 1. Structure of small leucine-rich repeat proteoglycan (SLRP) family members
SLRP memberClassNumber of LRRN-terminal Cys-rich clusterEar repeatGAG type/memberReferences
  1. †ECM2 has 15 leucine-rich repeats (LRRs), podocan-like protein 1 has 21 LLRs. ‡Asporin, proline/arginine-rich end leucine-rich repeat protein (PRELP) and opticin have no glycosaminoglycan (GAG) chains, but have potential sites for substitution by N or O-linked oligosaccharides (Iozzo 1999; Grover & Roughley 2001). C, cysteine; X, any other residue; CS, chondroitin sulfate; DS, dermatan sulfate; KS, keratan sulfate.

Biglycan

Decorin

Asporin

ECM2

I12CX3CXCX6CYesCS/DS (DKN, BGN)

(Iozzo 1999; Matsushima et al. 2000)

(Dammer et al. 1995; Schaefer & Schaefer 2010)

Fibromodulin

Lumican

PRELP

Keratocan

Osteomodulin

II12CX3CXCX9CYesKS

(Sommarin et al. 1998)

(Vogel 1994)

(Blochberger et al. 1992;

Corpuz et al. 1996)

(Plaas & Wong-Palms 1993)

(Bengtsson et al. 1995)

Epiphycan

Opticin

Osteoglycin

III8CX2CXCX6CYes

DS (EPYC)

KS (OGN)

O-linked oligosaccharides

(OPTC/EPYC)

(Reardon et al. 2000)

(Funderburgh et al. 1997;

Johnson et al. 1997)

Chondroadherin

Nyctalopin

Tsukushi

IV12CX3CXCX6-17CNoNot Examined – Potential sites for glycosylation

(Ohta et al. 2004)

(Neame et al. 1994)

Podocan

Podocan-like 1 protein

V20CX3-4CXCX9CNoNot Examined – Potential sites for glycosylation

(Ross et al. 2003)

(Mochida et al. 2011)

Due to the proteoglycan structure, SLRPs tend to localize in the extracellular matrix (ECM) after secretion and interact with ECM proteins. Initially, they were reported to regulate fibril assembly, organization and degradation by binding to structural ECM proteins such as different types of collagens (Kresse et al. 1997; Iozzo 1999; Keene et al. 2000; Neame et al. 2000; Reinboth et al. 2006; Kalamajski & Oldberg 2009). However, further studies elucidated that all members of the SLRP family directly regulate ligand-induced signalling pathways through binding to extracellular components such as their ligands and receptors. Members of the transforming growth factor (TGF)-β superfamily pathways, including the bone morphogenetic protein (BMP) pathway, are the major targets of the SLRP family (Yamaguchi et al. 1990; Moreno et al. 2005a; Morris et al. 2007). Recently, many studies have shown that SLRP members have the ability to regulate more than one signalling pathway. For example, decorin can bind to epidermal growth factor receptor (EGF-R), insulin-like growth factor receptor (IGF-IR), Wnt-I-induced secreted protein-1 (WISP-1), low-density lipoprotein receptor-related protein (LRP-1) and c-MET in addition to TGF-β and BMP4 and regulate their downstream signalling pathways (Iozzo et al. 1999; Desnoyers et al. 2001; Kolb et al. 2001; Kresse & Schonherr 2001; Chen et al. 2004; Brandan et al. 2006; Schaefer et al. 2007; Schaefer & Iozzo 2008; Goldoni et al. 2009; Inkson et al. 2009). On the other hand, Tsukushi (TSK), a recently identified member of the SLRP family, has the ability to bind at least with nodal/Vg1, BMP4/chordin, FGF8, Frizzled4, and Delta and regulate their corresponding signaling pathways: the nodal/Smad2, the BMP/Smad1, the FGF/MAP kinase, the canonical Wnt, and Notch/delta pathways in development (Morris et al. 2007; Ohta et al. 2011). The interacting proteins of the SLRP family and their regulated pathways are summarized in Table 2. Through such regulations, proteins of the SLRP family can influence cellular proliferation, growth, differentiation, survival, adhesion, migration, tumor growth and metastasis (Shimizu-Hirota et al. 2004; Nikitovic et al. 2008; Brezillon et al. 2009; Melchior-Becker et al. 2011).

Table 2. Functions of the small leucine-rich proteoglycans in signal transduction
SLRP memberTGF-β/Nodal/Smad2 pathwayBMP/Smad1 pathwayNotch pathwayMAPK/FGF pathwayEGF pathwayIGF pathwayWnt pathwayMet pathwayTLR pathwayPurinergic pathwayReferences
  1. BMP, bone morphogenetic protein; EGF, epidermal growth factor; IGF, insulin-like growth factor; MAPK, mitogen activating protein kinase; ND, not determined; SLRP, small leucine-rich repeat proteoglycan; TGF, transforming growth factor; TLR, Toll-like receptor.

Biglycan++NDNDNDNDNDND++

(Moreno et al. 2005a)

(Babelova et al. 2009)

Decorin++ND+++ND+NDND

(Yamaguchi et al. 1990)

(Schaefer et al. 2007)

(Iozzo et al. 1999)

(Goldoni et al. 2009)

Asporin++NDNDNDNDNDNDNDND

(Kizawa et al. 2005; Nakajima et al. 2007; Ikegawa 2008; Kou et al. 2010)

(Tomoeda et al. 2008)

Fibromodulin++NDNDNDNDNDNDNDND(Hildebrand et al. 1994)
Lumican+NDND++NDNDNDNDND(Albig et al. 2007; Chen et al. 2011; Nikitovic et al. 2011)
Keratocan+NDNDNDNDNDNDNDNDND(Kawakita et al. 2005)
Osteoadherin++NDND+NDNDNDNDND(Rehn et al. 2006, 2008)
Tsukushi++++NDND+NDNDND(Ohta et al. 2004, 2006, 2011; Kuriyama et al. 2006; Morris et al. 2007)

A majority of SLRP family members have been reported to be expressed during neural development and in adult neural tissues (Ohta et al. 2006; Le Goff & Bishop 2007), with some showing high levels of expression in ocular/eye tissues. The expression patterns and their molecular activities propose that SLRP family members function during neural development and maintenance through the regulation of multiple signaling pathways and their defects result in malfunction of neural systems. Recent studies have provided strong supporting evidence for their roles in neural development and maintenance, which are the focus of this review.

Germ layer specification

  1. Top of page
  2. Abstract
  3. Introduction
  4. Germ layer specification
  5. Organizer formation and neural induction
  6. Neural specification (neural crest specification)
  7. Neural precursor cell migration and differentiation
  8. Neural stem niches
  9. CNS injury response
  10. Functions in non-neural ocular/eye tissues
  11. Future direction
  12. Acknowledgments
  13. References

During embryonic development, three germ layers of ectoderm, mesoderm and endoderm are formed at the late blastula stage. These layers are the forerunners of all organs and tissues including neural tissues. In Xenopus, the germ layer formation occurs along the primary animal–vegetal axis of the embryo with the pigmented animal pole becoming ectoderm, the yolk-rich vegetal pole becomes endoderm, and the equatorial region becoming mesoderm (Schohl & Fagotto 2003; De Robertis & Kuroda 2004) (Fig. 2a). In association with the animal-vegetal axis, a second axis is created by cortical rotation after fertilization (Schohl & Fagotto 2003), resulting in dorso-ventral polarity. Both axes appear to rely on inductive interactions, which are generated by pre-localized maternal determinants. The vegetal hemisphere seems to be the main source of such determinants. Dorsal vegetal cells have the ability to induce animal cells to become dorsal mesoderm, while differentiating into endodermal tissue themselves (Schohl & Fagotto 2003).

image

Figure 2. Neural development and small leucine-rich repeat proteoglycan (SLRP)members. (a) Schematic drawing showing a Xenopus embryo at the blastula stage. Endoderm sends nodal signals (solid arrows) to induction mesoderm formation. Ectoderm forms in the animal cap. (b) Spemann's organizer (so) forms in the dorsal mesoderm. It sends dorsalizing signals (dashed arrows) to all three layers, and in the ectodermal layer, it induces neural tissue. (c) Neural crest cells originate at the neural plate border between neural plate (np) and epidermis (ep). (d) Schematic drawing depicts a differentiated neuron. (e) Neural stem cell niche in the subventricular zone of the brain.

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Tsukushi, a class IV member of the SLRPs, contains 12 LRRs. It was first identified in chick by signal sequence trap screening using a chick lens library (Ohta et al. 2004). TSK, which is a soluble molecule, was so named due to its expression pattern in chick embryos, as it resembles the shape of the Japanese horsetail plant, Tsukushi. Orthologues of chick TSK have been identified in mouse, Xenopus laevis, zebrafish, and human (Ohta et al. 2004). There is extensive sequence conservation between the different organisms with the exception of the C-terminus, which is more divergent (Ohta et al. 2006). In Xenopus embryos, localized mRNA of Xenopus-TSK (X-TSK) was observed during germ layer formation and early gastrulation, suggesting a role for X-TSK in germ layer formation and patterning (Morris et al. 2007). Indeed, X-TSK depletion results in a loss of endoderm, with the gut becoming significantly thinner as development progresses. On the other hand, its overexpression activates endoderm formation. At the same time, expression of the pan-mesoderm marker Xbra is increased, suggesting X-TSK has the ability to induce endoderm while inhibiting ventrolateral mesoderm formation. Interestingly, the endoderm inducing activity is mediated by co-ordinated regulation of three signaling pathways of the FGF8/MAP kinase, the BMP4/smad1 and the nodal/smad2, where X-TSK inhibits both the FGF8/MAP kinase and the BMP/smad1 pathways and activates the nodal/Smad2 pathway through direct binding with FGF8, BMP4, and Xnr2 ligands (Fig. 3). This combinatory regulation also inhibits ventro-lateral mesoderm formation. This co-ordination provides a synergistical effect on endoderm induction/formation (Morris et al. 2007).

image

Figure 3. Action of TSK in multiple signaling pathways. Tsukushi (TSK) can regulate five signaling pathways of the bone morphogenetic protein (BMP)4/Smad1, the Nodal-Vg1/Smad2, the fibroblast growth factor (FGF)8/mitogen-activated protein (MAP) kinase, the canonical Wnt, and the Delta/Notch pathways through interaction with their extracellular components. Depending on the developmental context, TSK seems to use a suitable combination of these pathways.

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Organizer formation and neural induction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Germ layer specification
  5. Organizer formation and neural induction
  6. Neural specification (neural crest specification)
  7. Neural precursor cell migration and differentiation
  8. Neural stem niches
  9. CNS injury response
  10. Functions in non-neural ocular/eye tissues
  11. Future direction
  12. Acknowledgments
  13. References

In Xenopus dorsal-ventral polarity establishment, the Nieuwkoop center is formed in the dorsal-vegetal part of the blastula and induces formation of the Spemann's organizer at the dorsal tip of the blastopore, called the dorsal marginal zone. The organizer dorsalizes the adjacent mesoderm and induces the neural tissues in the ectoderm above. This mechanism is conserved in vertebrates (Fig. 2b).

In chick, two alternatively spliced forms of TSK have been identified, C-TSK-A and C-TSK-B (Ohta et al. 2006). The expression and biochemical activities of the two forms are quite unique. Expression of C-TSK-A (originally referred to as C-TSK) begins in the area opaca and weakly in the hypoblast. At later stages, expression is concentrated in the Hensen's node, which corresponds to the Spemann's organizer in Xenopus and to the anterior primitive streak during gastrulation. Expression is also transiently seen in the newly forming somites and is eventually restricted to the tailbud by stage 7. On the other hand, C-TSK-B is expressed in the emerging primitive streak and the posterial marginal zone, which corresponds to the Nieuwkoop center in Xenopus (Ohta et al. 2006). After stage 4, expression of C-TSK-B is observed throughout the axial structures and peaks in the middle of the primitive streak. The inducing abilities of the organizer are mediated by secreted signaling molecules and their antagonists, in particular molecules of the BMP family, and their inhibitors such as chordin and noggin. The gain and loss of functional analysis using chick embryos showed that C-TSK-A functions as an inducer of organizer through inhibition of BMP activity. In Xenopus, C-TSK-A mRNA injected into the ventral marginal zone of the four-cell stage embryos induced secondary axis formation and dorsalization of ventral mesoderm. Animal cap experiments from Xenopus embryos injected with C-TSK-A mRNA demonstrated that C-TSK-A acts as a direct neural inducer through inhibition of BMP activity (Ohta et al. 2004). Furthermore, biochemical analysis revealed that C-TSK-A forms a ternary complex with BMP4 and chordin and synergistically inhibits BMP activity (Fig. 3). Interestingly, C-TSK-B also functions as a BMP inhibitor although it is significantly weaker than C-TSK-A. Both C-TSK-A and C-TSK-B bind directly to Vg1 (a member of the TGF-β superfamily and an activator of Smad2) to induce embryonic axis. C-TSK-B but not C-TSK-A is required for the induction of the Hensen's node by the middle of the primitive streak (Ohta et al. 2006).

Biglycan is a member in Class I of the SLRP family (Junghans et al. 1995). It is substituted with either one or two CS/DS side chains. Experiments in Xenopus showed that biglycan is able to regulate dorsal-ventral axis formation and induce a secondary axis by modulating the anti-BMP4 activity of Chordin (Moreno et al. 2005a). As observed in TSK, this is achieved by biglycan binding to BMP4 and Chordin, hence increasing the binding of BMP4 to chordin, the interaction critical in dorsal-ventral axis determination.

Decorin is a small leucine-rich CS/DS proteoglycan (Krusius & Ruoslahti 1986; Sawhney et al. 1991) that interacts extensively with ECM components including collagen and fibronectin. It binds to and sequesters TGF-β, inhibiting TGF-β signalling pathway (Yamaguchi et al. 1990). The immunofluorescence analysis of decorin in chick development (Zagris et al. 2011) identified high levels of expression in the epiblast cells adjacent to the primitive streak and in migrating mesodermal cells during gastrulation. At early neurula stages, decorin is strongly expressed in the endoderm as well as at the mesoderm-neural plate surfaces. Embryos developed abnormal anterior-posterior axis when they were treated with antibody against decorin. The authors suggested that decorin is essential for convergent extension cell movements during gastrulation. All observations indicate that multiple SLRP members are involved in organizer formation and neural induction.

Neural specification (neural crest specification)

  1. Top of page
  2. Abstract
  3. Introduction
  4. Germ layer specification
  5. Organizer formation and neural induction
  6. Neural specification (neural crest specification)
  7. Neural precursor cell migration and differentiation
  8. Neural stem niches
  9. CNS injury response
  10. Functions in non-neural ocular/eye tissues
  11. Future direction
  12. Acknowledgments
  13. References

During neural induction the ectoderm becomes divided into three main tissue types; neuroectoderm, epidermis and neural crest. The original model of neural induction proposed that a high level of BMP signaling was sufficient to repress neuroectoderm and induce epidermal cell fates (Wilson & Hemmati-Brivanlou 1995). While the neural inducing molecules such as noggin, follistatin and chordin can bind to BMPs and prevent their signaling, causing cells to adopt neural fates (Labonne & Bronner-Fraser 1998). Neural crest cells are specified at the border between the neuroectoderm and epidermis through co-ordination of suitable BMP activity with other signaling pathways such as Wnt and Notch/Delta pathways (Sasai & De Robertis 1997). X-TSK is expressed at the border of the neuroectoderm and surrounding epidermis and has been shown to control ectodermal patterning and neural crest specification by directly controlling BMP signaling and indirectly modulating BMP expression by altering the activity of Notch ligand Delta-1 (Fig. 3). X-TSK modulates the activity of X-Delta-1 in a dose dependent manner, activating it at lower X-TSK levels and repressing it at higher X-TSK levels. It is hypothesized that X-TSK has a pivotal role in neural crest formation by directly regulating BMP and Delta activities at the boundary between the neural and non-neural ectoderm (Kuriyama et al. 2006).

Neural precursor cell migration and differentiation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Germ layer specification
  5. Organizer formation and neural induction
  6. Neural specification (neural crest specification)
  7. Neural precursor cell migration and differentiation
  8. Neural stem niches
  9. CNS injury response
  10. Functions in non-neural ocular/eye tissues
  11. Future direction
  12. Acknowledgments
  13. References

After initial specification, neural precursor cells migrate to their final destination and differentiate into neurons and glial cells with complex processes. SLRPs are also involved in these processes.

Keratocan is an extracellular KS proteoglycan belonging to the SLRP family class II. Along with lumican and mimecan (or else osteoglycin), it facilitates formation of collagen fibrils, modulates hydration of corneal stroma and regulates corneal transparency (Liu et al. 1998; Pellegata et al. 2000; Wentz-Hunter et al. 2001). KS chains can inhibit cell adhesion, neurite outgrowth and trunk neural crest cell migration (Cole & Mccabe 1991; Perris et al. 1991; Mace et al. 2002). Keratocan mRNA is detected in the initial stages during chick embryogenesis in mid-brain and adjacent mesenchyme (Conrad & Conrad 2003). In addition, it is also expressed in subepidermal and sclerotomal mesenchyme adjacent to neural tube surrounding dorsal root ganglia and ventral trunk nerves. During mouse embryonic development, keratocan has been found to be expressed quite early, at embryonic day 13.5, in periocular mesenchymal cells of neural crest origin migrating towards developing cornea and sclera, while by day 18.5 it becomes restricted to corneal keratocytes but not in scleral cells (Liu et al. 1998). Also, Decorin is thought to be important for neural crest cell migration, since it was found to be highly expressed in pre-migratory and migratory neural cress cells (Zagris et al. 2011). Antibody-mediated inhibition of decorin function showed impeded neural crest cell migration (Zagris et al. 2011). Thus, migration of neural crest cells could be regulated by some SLRP members (Conrad & Conrad 2003). So far, little is known about the mechanism of SLRP-mediated neural crest cell migration. Lumican is known to participate in the inhibition of melanoma migration through α2β1 intergrin (Vuillermoz et al. 2004; Zeltz et al. 2010), suggesting that SLRPs may regulate neural precursor cell migration by a similar mechanism.

Tsukushi is expressed in differentiating brain in addition to its expression in early embryogenesis,. The TSK knockout mouse showed a complete absence of anterior commissure. aAC and pAC axons fail to link between right and left hemispheres (Ito et al. 2010). Dil labeling experiments indicated that although the aAC axons did grow out from the anterior olfactory nucleus and migrated along normal pathways they did not cross the midline, indicating that TSK is involved in the midline crossing (Fig. 3).

Decorin is widely expressed in normal adult rat brain, including the grey matter of neocortex, hippocampus, thalamus and cerebellum (Hanemann et al. 1993; Stichel et al. 1995; Kappler et al. 1998). In addition, its expression is also present in the grey matter neurons of the spinal cord (Hanemann et al. 1993). During postnatal rat brain development, decorin mRNA level is very low at P1 followed by a significant increase with levels peaking at P3. It then slowly decreases to the adult level (Kappler et al. 1998). This dynamic change in its expression indicates its possible role in the rat brain development. In the adult rat neural retina, decorin immunoreactivity was present throughout the neural retina but at highest levels in the ganglion cell layer and nerve fiber layer, with a moderate level of expression in the inner plexiform layer and inner nuclear layer (Inatani et al. 1999). During development, decorin is detected at moderate levels throughout the undifferentiated retina at E16. During postnatal stages, as ganglion cell differentiation and axon maturation occur, decorin level increased in the inner retinal layer such as the ganglion cell layer and nerve fiber layer, implying that decorin may be important for the differentiation of ganglion cells. Antibody-mediated inhibition of decorin function showed retinal progenitor cell disorientation (Zagris et al. 2011). Some reports indicate the negative effect of decorin on neural differentiation. For example, neurite outgrowth was inhibited when sensory neurons were cultured on substrata containing laminin and decorin compared with laminin alone (Lemons et al. 2005). However, this inhibition was only temporary (3 h) and it was soon followed by adaption. In 20–24 h culture, the rate of axon growth was indistinguishable between proteoglycan/laminin and laminin alone substrata. Barkho et al. performed gene expression profiling analysis using neurogenic astrocytes and non-neurogenic astrocytes and found that decorin is expressed at significantly higher levels in non-neurogenic astrocytes (Barkho et al. 2006). Their functional analysis showed recombinant decorin significantly reduced neuronal differentiation of adult neural stem/progenitor cells (NSPCs) co-cultured with astrocytes. It was proposed that decorin might inhibit neuronal differentiation by antagonizing TGF-β2, which was found to be a necessary component of the combined factors that strongly promote NSPC differentiation (Barkho et al. 2006).

Biglycan is also expressed in adult rat brain (Stichel et al. 1995). Liang et al. (1997) showed that biglycan immunoreactivity could be detected in the nuclei of adult rat spinal cord and cerebrum sections. They also identified the signal sequence responsible for nuclear localization. Biglycan has also been shown to temporarily inhibit neurite outgrowth of sensory neurons (Lemons et al. 2005). In addition, biglycan has a well-known ability to strongly enhance survival of embryonic rat neocortical neurons in vitro (Junghans et al. 1995; Koops et al. 1996), and its CS/DS chains are important in its neuron survival-supporting function (Kappler et al. 1997).

In addition to the roles of SLRP family members in embryonic neural development, they also contribute to maintenance of the nervous system through adult neural stem regulation and CNS injury response.

Neural stem niches

  1. Top of page
  2. Abstract
  3. Introduction
  4. Germ layer specification
  5. Organizer formation and neural induction
  6. Neural specification (neural crest specification)
  7. Neural precursor cell migration and differentiation
  8. Neural stem niches
  9. CNS injury response
  10. Functions in non-neural ocular/eye tissues
  11. Future direction
  12. Acknowledgments
  13. References

The neural stem cell niche is an area where neural stem cells reside after the completion of embryonic development. The balance of stem cell quiescence and proliferation is controlled by signals from the microenvironment and cell–cell interactions in the stem cell niches. In the amphibian and fish retina, there is a neural stem cell niche, which is located at the peripheral side of the retina, called the ciliary marginal zone (CMZ). Retinal stem cells are located at the most peripheral edge of the CMZ, which continuously produce neurons and glial cells throughout the whole life of the animal (Bilitou & Ohnuma 2010). Chick and mammals also have a similar structure in the peripheral region of retina, which is called the ciliary body (CB). Chick CB functions as a stem cell niche. However, the role of mouse CB is under active discussion although it has potential to express markers of differentiated retinal neurons.

C-TSK-A is expressed in the peripheral region of the chick eye at E6. C-TSK-B is expressed in the adjacent ciliary/iris epithelium (Ohta et al. 2011). In the adult mouse, M-TSK is expressed in the inner nuclear layer of the CB and the lens epithelium. In TSK−/− mice, both the ventral and dorsal CB appeared larger than in wild type mice (Ohta et al. 2011). The canonical Wnt pathway regulates retinal stem cell proliferation (Kubo & Nakagawa 2008). Wnt2b and Frizlled4 expression was increased in the TSK−/− mouse eye and the TSK knockout showed enlargement of ventricular space of the brain, which is similar to activation of the canonical Wnt pathway. Given the expression pattern of Wnt receptors, Fzd1, 3 and 4, it was hypothesized that Wnt2b and C-TSK-B could perhaps functionally interact with each other. Indeed, it was found that TSK inhibits Wnt2b activity both in vitro and in vivo, through direct TSK binding to Fzd4 (Fig. 3). TSK is also specifically expressed in other adult neural stem cell niches of the subventricular zone of brain and the subgranular zone in the hippocampus (Fig. 2e). These observations indicate that TSK regulates neural stem cells as a niche molecule through its role as a Wnt signaling inhibitor (Ohta et al. 2008, 2011).

Opticin is a member of the class III SLRP family, sharing high protein homology in the LRR domain with epiphycan and osteoglycin (Reardon et al. 2000). Opticin contains a cluster of O-linked oligosaccharides, instead of glycosaminoglycan side chains (Le Goff et al. 2003). Reardon et al. (2000) firstly identified opticin as a 45-kDa protein component of the eye, strongly associated with the collagen fibrils of the bovine vitreous humor (Reardon et al. 2000). Similarly to decorin, opticin has been found to exist as a stable dimer in solution, probably through interaction of its LRR domains (Le Goff et al. 2003; Scott et al. 2003). Opticin expression is mostly localized in the eye and specifically to the non-pigmented epithelium of the CB in mice (Takanosu et al. 2001; Bishop et al. 2002). Takanosu et al. demonstrated opticin expression in the 15.5-dpc mouse embryonic eye at the anterior tip of the developing neuroretina, while in the 17.5-dpc embryonic eye, opticin mRNA was expressed in CB cells between the iris and the neuroretina. In the same study, CB differentiation is shown to have started before stage 15.5 dpc and thus it is concluded that opticin mRNA could represent a marker for CB differentiation (Takanosu et al. 2001). As the CB epithelium harbors neuronal progenitors cells, which have a potential to differentiate to retinal cells (Ahmad et al. 2000; Tropepe et al. 2000), opticin may have an influence in the above process. Also TGF-β2/decorin pathway may be involved in regulating NSPC neuronal differentiation in the adult stem cell niche (Barkho et al. 2006).

CNS injury response

  1. Top of page
  2. Abstract
  3. Introduction
  4. Germ layer specification
  5. Organizer formation and neural induction
  6. Neural specification (neural crest specification)
  7. Neural precursor cell migration and differentiation
  8. Neural stem niches
  9. CNS injury response
  10. Functions in non-neural ocular/eye tissues
  11. Future direction
  12. Acknowledgments
  13. References

Decorin has also been implicated to have important roles in the recovery following CNS injuries. Decorin is rapidly upregulated within a wide area around the lesion in injured adult rat brain, primarily by astrocytes (Stichel et al. 1995). This high level of decorin expression persisted for at least up to 6 months after lesion. Experiments in which inner retinal layers were seriously damaged with transient ischemia showed that decorin level underwent a series of changes following the ischemic injury and reperfussion (Inatani et al. 1999). The level of decorin mRNA stayed the same in the first 3 h after reperfussion. From 6 h after cessation of ischemia, the level of decorin mRNA decreased and reached the minimum at 24 h, which may be the result of a loss of decorin-producing ganglion cells. However, this is followed by a recovery to its original levels or even higher at 7 days after reperfussion. The increased expression of decorin may contribute to the repair process in damaged neural retina. Supporting this, decorin has been shown to suppress inhibitory scar formation (Logan et al. 1999) and promote axon growth following CNS injuries via some mechanisms. Decorin infusion suppressed the expression of CS proteoglycans that inhibit axon regeneration in adult CNS, including neurocan, brevican, phosphacan and NG2, and promote axon growth in an adult rat spinal cord injury model (Davies et al. 2004). In addition, it suppresses semaphorin 3A expression (Minor et al. 2011), one of the CNS scar associated axon growth inhibitors, both in adult rat cerebral cortex injury sites and in primary leptomeningeal fibroblasts in vitro in an ErbB4 and STAT3 dependent manner. Decorin can also directly promote neurite extension within CS proteoglycan or myelin rich environments (Minor et al. 2008).

Injury to the adult rat brain also causes massive and persistent upregulation of biglycan expression in the transaction site, but its expression is more restricted than the area of decorin upregulation (Stichel et al. 1995), indicating their possibly different roles in CNS injury. It is deposited extracelluarly in sheet-like structure. Another model where kainic acid was injected into the mouse hippocampus causing recurrent seizures (Motti et al. 2010) showed that biglycan is present at high levels both inside astrocytes and in the extracellular matrix at 2 weeks after injection, suggesting biglycan possibly being synthesized by activated astrocytes after neuronal injury. At 6 months after kainic acid injection, biglycan was still elevated in regions where neuronal loss occurred, contributing to a persistent glial scar.

Functions in non-neural ocular/eye tissues

  1. Top of page
  2. Abstract
  3. Introduction
  4. Germ layer specification
  5. Organizer formation and neural induction
  6. Neural specification (neural crest specification)
  7. Neural precursor cell migration and differentiation
  8. Neural stem niches
  9. CNS injury response
  10. Functions in non-neural ocular/eye tissues
  11. Future direction
  12. Acknowledgments
  13. References

It is well known that SLRP family members are very highly expressed in ocular tissues and their mutations are known to cause several eye diseases (Table 3). Here, we summarize their functions in non-neural ocular tissues.

Table 3. Human disorders caused by defects in small leucine-rich repeat proteoglycan (SLRP) family members
SLRPExpression/mutationDiseaseReferences
Biglycan

Overexpression

Overexpression

Gastric cancer

Kidney disease

(Wang et al. 2011)

(Stokes et al. 2000)

Decorin

Truncating mutation

Decreased expression

Congenital stromal

dystrophy of the

cornea

Atherosclerosis

(Bredrup et al. 2005)

(Singla et al. 2011)

AsporinFunctional polymorphismOsteoarthritis(Kizawa et al. 2005)
FibromodulinC.917G>AHigh myopia(Majava et al. 2007)
Lumican

c.1567 C/T polymorphism

Leu199Met missense variant

c.469A4G/p.M157V mutation

High myopia

Amyotrophic lateral

sclerosis

(Lin et al. 2010)

(Majava et al. 2007)

(Daoud et al. 2011)

PRELP

Not known

Overexpression

High myopia

Progeria

Brain tumors

(Majava et al. 2007)

(Lewis 2003)

(Castells et al. 2010)

KeratocanN247S, Q174XCornea plana(Pellegata et al. 2000)
Opticin

c.530C4G/p.T177R

Arg229Cys

High myopia

AMD

(Majava et al. 2007)
Nyctalopin

85-108del24nt,452C[RIGHTWARDS ARROW]T,464^465ins21nt,551T[RIGHTWARDS ARROW]C,

556-618del50ins3nt,619^620ins9nt,628^629ins9nt,

638T[RIGHTWARDS ARROW]A, 647A[RIGHTWARDS ARROW]G, 695T[RIGHTWARDS ARROW]T, 792C[RIGHTWARDS ARROW]G,

854T[RIGHTWARDS ARROW]C, 893T[RIGHTWARDS ARROW]C, 1049G[RIGHTWARDS ARROW]A

Congenital stationary

Night blindness

(Bech-Hansen et al. 2000)
PodocanOverexpression

HIV associated

nephropathy

(Ross et al. 2003)

Small leucine-rich repeat proteoglycan family members are highly expressed in ECM rich tissues such as connecting tissues. Some ocular tissues such as cornea and vitreous largely consist of ECM proteins such as collagens. Indeed, some SLRPs are very highly expressed in these ocular tissues. Fibromodulin, keratocan and lumican, which all contain KS side chains, are highly expressed in both differentiating cornea and the adult cornea and have been shown to be involved in the development and maintenance of corneal transparency (Hart 1976; Cornuet et al. 1994; Tanihara et al. 2002; Chen et al. 2010; Ali et al. 2011). Their high importances in the corneal development has been demonstrated by analyses of their gene knockout animals. Keratocan knockout mice show a phenotype of flattened corneal curvature along with thin corneal stroma, which resembles the inherited human disease corneal plana (Liu et al. 2003). While lumican-null mice develop corneal opacity in addition to skill fragility (Chakravarti et al. 1998). Furthermore, Yeh et al. (2008) demonstrated that knockdown of keratocan in zebrafish led to enhanced apoptosis and embryonic lethality, suggesting that there might be more critical functions of the Keratocan for normal zebrafish development in addition to its ECM formation roles.

Opticin expression has been previously found in adult human iris, cornea, vitreous, choroid and retina (Friedman et al. 2000; Hobby et al. 2000). Friedman et al. (2002) further demonstrated opticin protein expression in the optic nerve and speculated that opticin, being an ECM protein, probably traveled from the eye to the optic nerve. Initially, it has been shown that opticin is associated with the process of collagen fibrillogenesis in the vitreous gel, therefore being of high structural importance in the formation and maintenance of the vitreous (Bishop 2000). Furthermore, Hindson et al. demonstrated that opticin binds CS and HS proteoglycans involving type XVIII collagen, thus linking the vitreous collagen fibrils to the inner limiting lamina and acting as a “molecular glue” at the vitreoretinal adhesion (Hindson et al. 2005; Le Goff & Bishop 2008). Apart from the structural roles mentioned above, opticin has also been reported to bind to retinal growth hormone, specifically at the retinal ganglion cells, where it may modulate growth factor-like actions in retinal development (Sanders et al. 2005).

Future direction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Germ layer specification
  5. Organizer formation and neural induction
  6. Neural specification (neural crest specification)
  7. Neural precursor cell migration and differentiation
  8. Neural stem niches
  9. CNS injury response
  10. Functions in non-neural ocular/eye tissues
  11. Future direction
  12. Acknowledgments
  13. References

Biological studies, including recent advances in system biology, clearly indicate that almost all developmental events are governed by combination of multiple signaling pathways. As shown in Table 2 and Figure 3, SLRP family members have the ability to regulate almost all signaling pathways involved in development. Until now, almost all studies have been elucidating the role of SLRP family members in the context of a single signaling pathway. Probably, such an affected pathway may have the most influential role in the SLRP-mediated event. However, these studies may not show the exact function of the proteins in the complex developmental context. Therefore, it is important to know exactly what combination of signaling pathways are regulated by the SLRP family member in each developmental event. It is likely that each SLRP family member dynamically regulates a distinct combination of signaling pathways in a context dependent manner. Next, it is important to elucidate the biological significance of co-ordination of multiple pathways. The study of TSK in germ layer formation showed that the combination of three pathways provided much stronger effect than those produced by modulation of the individual pathway (Morris et al. 2007). Probably, through suitable combination, it might be possible to potentiate some weak signaling at specific areas and at specific times during development. Interestingly, SLRP family members are not highly diffusible and tend to stay in extracellular matrix. Members such as TSK and opticin are known to localize at stem cell niches (Le Goff & Bishop 2007; Ohta et al. 2008). The proteins that localize in the niches may create a microenvironment for stem cell maintenance through combinatory potentiation of localized multiple signaling activities. Finally, it is important to know the mechanism of multiple signaling co-ordination. A SLRP protein may simultaneously bind to more than one signaling component and regulate multiple signaling pathways, while binding of another SLRP protein with a partner may compete its binding with another binding protein. Ohta et al. (2004) showed that TSK simultaneously binds with BMP and chordin and synergistically potentiates chordin's BMP inhibitory activity during organizer formation. Therefore, more dynamic mechanistic regulation might be happening. These observations suggest that extracellular protein function is dynamically and co-ordinatedly regulated by SLRP family members and such regulation of extracellular signaling network must be important in biological processes.

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  1. Top of page
  2. Abstract
  3. Introduction
  4. Germ layer specification
  5. Organizer formation and neural induction
  6. Neural specification (neural crest specification)
  7. Neural precursor cell migration and differentiation
  8. Neural stem niches
  9. CNS injury response
  10. Functions in non-neural ocular/eye tissues
  11. Future direction
  12. Acknowledgments
  13. References
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