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Glycans in Regeneration Ponnusamy Babu* Glycomics and Glycoproteomics, Centre for Cellular and Molecular Platforms, NCBS-TIFR, GKVK Post, Bangalore 560065, India ABSTRACT: Glycans participate in many key cellular processes during development and in physiology and disease. In this review, the functional role of various glycans in the regeneration of neurons and body parts in adult metazoans is discussed. Understanding glycosylation may facilitate research in the field of stem cell biology and regenerative medicine.
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occur during regeneration is still at infancy, despite some major breakthroughs such as in vitro reprogramming of adult fibroblast cells into induced pluripotent stem (iPS) cells using a cocktail of transcription factors and small molecule activators and inhibitors of various signaling pathways.10−12 Wound healing, cell−cell communication, proliferation, cell migration, cell-ECM interactions, and differentiation are some of the processes involved during regeneration.13 These events are orchestrated by synchronized interaction of growth factors, ECM machinery, cell surface receptors, downstream signaling molecules, and transcription factors. Although a number of studies have been conducted on stem cell biology and their regulation at the level of gene expression and transcriptional regulation, comparatively fewer studies have been reported on the role of complex carbohydrates in regeneration. A number of excellent review articles have been published on gene expressions in regeneration,14−17 which therefore will not be considered in this article. Complex carbohydrates or glycans are known to play important functions in a number of cellular processes including development, cell−cell communication, cell migration, homeostasis, and disease.18,19 An excellent review article has been published recently on the glycans present on the stem cells.20 Since there is no comprehensive article dealing with glycans and regeneration, this review article looks at the role of various glycans in the regeneration of cells and tissues across metazoans.
egeneration, defined broadly as the regrowth of body part(s) following injury, is a process by which all organisms have evolved to maintain their structural integrity and shape. There are different forms of regenerative processes observed throughout metazoans: replacement of cells, replacement of organs, and regrowth of the whole animal from a cell mass (Hydra reaggregation).1 Regeneration can occur by two processes: epimorphosis and morphallaxis.2 In epimorphosis, cellular proliferation is required for tissue regrowth as in human liver regeneration3 and Planarians, whereas regeneration of the lost part through remodeling of preexisting cells without proliferation is called morphallaxis, as in Hydra.4 “If there were no regeneration there could be no life and if everything regenerated there would be no death.”5 The regenerative capacity of metazoans varies depending upon their life cycle stage (embryonic or adult) and evolutionary period. For example, higher metazoans begin their life from a single cell and seem to lose the capacity to regenerate as they develop into adults. However, invertebrates such as Hydra and Planarians retain their regenerative capacity even at adult stage, fundamentally due to high abundance (25−30% total number of cells) of pluripotent stem cells and their regulation.6 In fact, the cell populations of Hydra are primarily composed of stem cells.7 Due to their remarkable regenerative capacity, lower invertebrates are excellent model systems to study cellular and molecular processes involved in regeneration as compared to vertebrates such as newts and salamanders or fish, which have limited capacity to regenerate feet or fins, respectively. Regeneration has been the subject of curiosity-driven research since the Darwinian period. However, only since the middle of the 20th century have the cellular and molecular players involved in this event been revealed as a result of the molecular biology revolution and development of other techniques. In recent years, there has been a renewed interest in stem cell biology and regeneration because of the tremendous potential in stem cell replacement therapy and regrowth of organs for treatment of various diseases.8,9 However, our understanding of various molecular events that © 2013 American Chemical Society
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GLYCAN DIVERSITY Glycans are expressed as conjugates of polypeptides, lipids, and small molecules. The huge diversity of glycans on glycoconjugates is due to various factors such as multiple monosaccharide building blocks, linkage sites, and stereochemistries.21,22 The Special Issue: Stem Cell Biology and Regenerative Medicine Received: October 11, 2013 Accepted: November 29, 2013 Published: November 29, 2013 96
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Lipid glycosylation in the secretory pathway is a prevalent modification and creates glycolipids (glycosphingolipids) that include the sialic acid-bearing gangliosides.28 Other forms of glycosylation occur outside of the secretory pathway. In most eukaryotes N-acetylglucosamine has been found linked to serine and threonine residues (O-GlcNAc) of several cytoplasmic and nuclear proteins.29 In recent years, a plethora of studies have reported the expression and function of O-GlcNAc-modified proteins and transcription factors.30−32 The glycans and their biosynthetic enzymes modulate various cellular events. For example, overexpression of GlcNAc transferase-III (GnT-III) enzyme, which adds bisecting GlcNAc residue to the mannose residue of N-glycans in E-cadherin and integrins, enhances cell−cell adhesion and decreases cell− extracellular matrix (ECM) adhesion interaction, leading to suppression of cancer metastasis. On the other hand, overexpression of GnT-V, which incorporates GlcNAcβ16Man, promotes metastasis by loss of contact inhibition.33,34 Similarly, lack of core fucosylation of EGFR leads to dysfunction of EGF signaling and suppression of cell growth.35 Various sulfated polysaccharides from plants and animals including heparan sulfate proteoglycans regulate tissue remodeling and apoptosis through the caspase pathway.36 A number of studies also reported the role of glycosaminoglycans in cell differentiation.37 Despite the tremendous variety of glycans found in metazoans, only a very few glycans have been directly implicated in regeneration. The following sections discuss the functions of specific glycans in regeneration.
diversity of glycan structures is also contributed to by nontemplate driven biosynthesis of the glycans, the concentration and transport of active sugar-nucleotides across membranes, and the expression of glycosyltransferases and glycosidases in a tissue-specific manner. The glycan structures are grouped into subclasses based on their attachment to their conjugates and terminal atom. N-Glycans, O-glycans, O-GlcNAc, and glycosaminoglycans (except hyaluronic acids) are attached to proteins, whereas in glycosphingolipids and GPI-anchored proteins the glycan moieties are conjugated to lipids23 (Figure 1).
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POLYSIALIC ACIDS AND NEURON REGENERATION Polysialic acid (PSA) is a linear homopolymer of α 2,8-linked N-acetylneuraminic acid (NeuAc), often primed on α2,3NeuAc termini of the N-glycans. PSA-containing N-glycans are expressed selectively on the fifth immunoglobulin-like domain of neural cell adhesion molecule (NCAM).38,39 The biosynthesis of PSA is mediated by two sialyl transferases, ST8siaII and ST8siaIV, and their expression has been shown to directly correlate with the function of PSA in the brain.40 All three isoforms of NCAM (180, 140, and 120 KDa) express PSANCAM in a development-specific manner.41 During early neuronal development PSA is highly expressed and is downregulated when the developmental events stabilize cell interactions in adults.42−44 Stem cell populations present in the subventricular zone (SVZ) produce precursor neuronal cells by asymmetric division. Of these, only those neuronal progenitor cells expressing PSA migrate along the rostral migratory stream (RMS) to replenish interneurons of the olfactory bulb.45,46 On removal of PSA by specific endosialidase N, the neuroblasts were unable to migrate from the germinal zone, resulting in reduced size of the olfactory bulb, as observed in NCAM-deficient mice. During this tangential cell migration PSA has been suggested to facilitate adhesion and de-adhesion using each other as substrate.47,48 The adult mammalian CNS is refractory to change and thus unable to repair upon injury or disease. This failure of axon regeneration after lesion is due not only to the intrinsic inability of the CNS axon to grow but also the nonpermissive environment of the scar. At the lesion, there is a transient expression of PSA that supports sprouting, but soon the growth cones adapt to swollen dystrophic morphology, inhibiting the growth.49 Interestingly, the most persistent axonal growth occurs at a small subpopulation of astrocytes expressing PSA
Figure 1. Structure of various glycans involved in regeneration.
The N-glycans are linked to proteins via the N-atom of an asparagine (N) residue with a consensus sequence N-A-S/T, where ‘A’ can be any amino acid except proline.24 The Nglycans are further classified as high mannoses, hybrid, and complex glycans based on their structural complexity. The structural complexity of the N-glycans varies in general from lower to higher metazoans. While the deuterostome glycans are abundant with sialic acids, the presence of sialic acids in lower metazoans has not been reported so far. Similarly, the antennary structures containing LacNAc repeats are more common in mammalian N-glycans, whereas LacNAc or LacdiNAc repeats are rare in lower metazoans. Unlike the N-glycans, which have a common chitobiose core, the O-glycans consist of multiple core structures and are attached to S/T residues via the oxygen atom of the Nacetylgalactosamine. For example, the mammalian O-glycans have been shown to contain up to eight designated core structures.25 O-Glycans may comprise up to 80% of the molecular weight of proteins such as in mucins.26 The glycosaminoglycans (GAGs) are also attached to the proteins through an ‘O-linkage’ of the S/T amino acid; however, these glycans are linear in nature and consist of disaccharide repeats.27 On the basis of the disaccharide composition, GAGs are further categorized into heparan sulfate, chondroitin sulfate, dermatan sulfate, keratin sulfate, and hyaluronic acids. 97
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Figure 2. Expression patterns of PSA and CS-GAG during nerogenesis and CNS axon regeneration. The cartoon illustrates regeneration of a CNS axon through a lesion site. (a) PSA expression during development promotes axon regeneration. (b) Inhibitory environment of CS-GAG expression at the scar tissue renders nonpermissive axonal regrowth. (c) Engineered overexpression of PSA and suppression of CS-GAG expression promotes CNS axon regeneration. (d) Engineered expression of PSA on grafted Schwann cells enhances their regeneration-promoting effect.
transiently. On sustained expression of high levels of PSA by transfecting the scar astrocytes using viral vector encoding polysialyltransferase (PST), a substantial portion of severed corticospinal tract axons were able to migrate through a spinal injury site. Furthermore, induced PSA expression in a path extending from the SVZ to a lesion site increased recruitment of neuronal progenitor cells.50 However, after exiting the PSAexpressing scar, the regenerating axons were unable to continue growing in the distal stump probably because of the inhibitory nature of the PSA-negative environment (Figure 2b). The other approach to augment axon regeneration is by implanting engineered PSA-expressing Schwann cells (SCs) at the scar site. The PST-overexpressing SCs migrated across the lesion up to 4.4 mm within adjacent host tissue, and there was extensive serotonergic and corticospinal axon in-growth within the implants. Animals receiving PST-SCs also exhibited improved functional outcomes (Figure 2d). This study provides evidence for the role of PSA in progenitor and SC migration as well as axon regeneration in mice models.51 Recent studies involving human adult dental pulp stem cells and stem cells derived from human exfoliated deciduous teeth showed better therapeutic benefits for extreme conditions of spinal cord injury compared with transplantation of human bone marrow stromal cells or skin-derived fibroblasts in rat.52
In addition to PSA-containing N-glycans, glycans containing Fucα(1-2)Gal epitope has been implicated in modulation of neurite outgrowth and long-term memory. The Fucα(1-2)Gal carbohydrate on synapsin impacts its expression and half-life in presynaptic terminals. Defucosylation of neurons with 2deoxygalactose led to stunted neurite outgrowth in cell cultures, whereas less pronounced retraction is observed in synapsin deficient mice presumably due to absence of synapsin.53 However, the structure of glycan containing Fucα(1-2)Gal has not been established.
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CHONDROITIN SULFATES AND AXONAL GROWTH AND GUIDANCE The chondroitin sulfates (CS) are linear sulfated glycosaminoglycans, composed of GlcAβ1-3GalNAc disaccharide repeats, attached to core proteins. The structural variability of the CS depends on the sulfation pattern and is categorized into CS-A (GlcA-4SGalNAc), CS-C (GlcA-6SGalNAc), CS-D (2SGlcA6SGalNAc), and CS-E (GlcA-4S,6SGalNAc). During development the CSPGs act as guidance cues or inhibit axon growth at various points along neuronal pathway.54,55 In the developing mammalian retina, gradual regression of chondroitin sulfate helps control the onset of ganglion cell differentiation and initial direction of their axons.56 In vitro study involving embryonic DRG neurons, 98
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Figure 3. Bright field and fluorescence images of regenerating aggregated cell mass in Hydra medium alone or with LTA-FITC and UEA-I-FITC, respectively. In control, all aggregates were able to regenerate into full grown Hydra, whereas LTA- and UEA-I treated aggregates failed to regenerate.
whereas in the glial scar, CS-2, CS-6 (CS-C), and CS-4,6 (CSE) were overexpressed. Despite the lack of consensus, most of the studies support that the sulfation pattern on CS-E (GlcA4S,6SGalNAc) has major influence on the inhibition of neurite extension after a CNS injury. For example, Hsieh-Wilson and co-workers showed, using chemically synthesized CS-E containing monomers and polymers, that CS-E present on the cell surface or coated on the coverslips promotes neuronal outgrowth by recruiting brain-derived neurotrophic factor (BDNF) or Midkine growth factors.70,71 However, when CSE is present in the solution, it inhibits neurite growth by sequestering growth factors, which are ligands for protein tyrosine phosphatase PTPσ receptor and its downstream signaling.72,73 Recently, Swarup et al. showed the role of CSE in directing outgrowth of dorsal root ganglians using cell choice assay on various CS printed on a poly-L-lysine surface.74 Supporting these results, a number of studies have reported overexpression of CS 6-sulfotransferase-1 and CS 4-sulfotransferase in the glial scar.75−79 These results suggest that sulfation code as well as multivalent interactions are important for the neuronal regeneration. The CSPGs are thought to inhibit regeneration of neurons through nonspecific contact inhibition, through their acidic GAG chains, as well as through their receptor mediated signaling mechanisms. Recent findings suggest that two members of the LAR subfamily of PTPs are the functional receptors for CSPG molecules.80,81 The LAR subfamily is composed of three homologues in vertebrates: LAR, PTPσ, and PTPδ. Mice lacking LAR phosphatase domains exhibit spatial
retinal neurons, and forebrain neurons cultured on a gradient of laminin and CSPGs showed that all of the neurons were able to extend up to a certain gradient, with retinal neurons navigating furthest.57 This work showed not only that different populations of neurons respond to CSPGs differently but also that neurons are capable of outgrowth on CSPGs. The adult neurons, unlike their embryonic counterparts, cease growing and form an unusual type of dystrophic ending. In the adult nervous system, high levels of CSPGs are found in perineuronal nets, where they are thought to stabilize synaptic connections. Removal of the chondroitin sulfate GAG chains using chondroitinase ABC (cABC) restores ocular dominance plasticity in the adult visual cortex of rats.58 The regeneration of a mammalian CNS axon after injury is inhibited by intrinsic and external factors in the extracellular matrix (ECM). The CSPGs are the major component responsible for inhibition of axon sprouting in addition to the secreted proteins such as Semaporin 3,59 Ephrin-B3/Eph-B2,60 and Slit/Robo.61 It has been well established that at the site of a glial scar various CSPGs are overexpressed.62−66 However, the embryonic reactive glia do not upregulate the CSPGs,67,68 and there is a minimal upregulation of CSPGs on reactive glia in cold blooded animals.69 A number of in vitro and in vivo studies have reported specificity of CS-GAGs toward inhibition of axon sprouting and path finding after CNS injury. Quantification of the CS-GAGs in uninjured and injured brain (scar tissue) using fluorophoreassisted carbohydrate electrophoresis demonstrated that the dominant CS-GAG in the uninjured brain is CS-4 (CS-A), 99
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learning impairment and hyperactivity.82 PTPσ-deficient mice exhibit severe growth retardation, high neonatal mortality, and other neurological defects, including motor dysfunction, defective proprioception, hippocampal dysgenesis, abnormal pituitary development, and thinning of the corpus callosum and cerebral cortex.83,84 The PTPδ knockout mice also exhibited marked motor dysfunction and impaired visuospatial processing with low survival rates.85 The Nogo receptors NR1−3, GPIanchored proteins, have been shown to bind to the CSPGs, and the combined deletion of NgR1 and NgR3, but not NgR1 and NgR2, was able to overcome the CSPG-mediated inhibition of neurite elongation and promoted regeneration of injured optic nerves in adult mutant mice. Simultaneous ablation of PTPσ with NgR1 and NgR3 further promoted regrowth of lesioned optic nerves in mutant mice. Thus, the CSPG receptors mediate some of the axon growth-inhibiting effects in the reactive astrocytes. The CSPGs and their receptors mediate inhibition of axon growth by downstream signaling involving AKT/PKB, glycogen synthase kinase 3β (GSK-3β), Rho, protein kinase C, and others.86−91
and embryonic limb formation.97,98 It begins with formation of a blastema, an undifferentiated cell mass, at the amputated stump. The blastema is formed by cellular dedifferentiation of major cell types including fibroblasts, cells of skeletal tissue, muscle cells, Schwann cells, and vascular endothelial cells.99 Recent studies have identified a growth factor like protein nAG as a ligand for a GPI-anchored receptor Prod-1, a key receptor involved in regeneration of the limbs in Newts.100 During the early, nerve-dependent phase of Newt forelimb regeneration, the synthesis of glycosaminoglycans is maximum. Hyaluronic acid synthesis is high within the first week followed by chondroitin sulfate synthesis, which increases steadily, reaching very high levels during chondrogenesis.101 Since nerves are necessary to promote the regenerative process, quantitation of various GAGs in dedifferentiating tissues showed that there is 50% reduction in the production of GAGs in denervated newts as compare to normal regenerative newts.102 The axon regeneration influences GAG production, which in turn helps blastema formation and proliferation by presenting the growth factors.103
GANGLIOSIDES AND AXON REGENERATION The gangliosides, sialic acid-bearing glycosphingolipids, are expressed at high abundance in the brain. Altered expression of the gangliosides results in a number of neural disorders, including seizures and axon degeneration. The brain gangliosides function by interacting with myelin-associated glycoprotein (MAG). MAG, on the innermost wrap of the myelin sheath, binds to gangliosides GD1a and GT1b on axons.92 The MAG−ganglioside binding ensures optimal axon−myelin cell− cell interactions, enhances long-term axon−myelin stability, and inhibits axon outgrowth after injury. Evidence from in vitro studies using sialidase treatment supports the reversal of MAGmediated axon outgrowth inhibition and enhanced motor axon outgrowth in vivo.93
O-FUCOSE AND REGENERATION The gene encoding the Notch receptor was discovered in fruit flies nearly 100 years ago where a partial loss of function (haplo insufficiency) resulted in irregular structures or notches in the wing margin of flies.104,105 Notch is a ∼300 KDa transmembrane protein consisting of a large portion of the extracellular domain of 36 tandem EGF repeats, many of which are modified with O-fucose by the enzyme protein-Ofucosyltransferase1 (Pofut1). Elongation of O-fucose into NeuAcα2-3/6Galβ1-4GlcNAcβ1-3Fuc tetra saccharide is initiated by glycosyltransferases from the Fringe family of genes in mammals. The binding of ligands Delta, Jagged, or Serrate to Notch receptor initiates a series of reactions leading to release and nuclear localization of the Notch intracellular domain (NICD), which together with transcriptional regulators modifies expression of target genes during development,18 regeneration, and disease. Elimination or reduction of levels of Pofut1 by RNAi in D. malanogaster and mice produced phenotypes similar to Notch, emphasizing the importance of O-fucose addition in Notch signaling.106,107 Cells lacking Pofut1, which added O-fucose residue to S/T in the extracellular domains of epidermal growth factor (EGF) repeats, seems to affect the binding of Notch with its ligand Delta. Pofut1 has been shown to have a chaperon-like property that helps expression of Notch in flies but not in mice. Similarly, Fringe, a GlcNAc transferase that elongates O-fucose, appears to modulate Notch-ligand binding in flies. Elongation beyond a trisaccharide (Galβ1-4GlcNAcβ1-3Fucose) is necessary for Fringe action in a mammalian cell system, which is not the case in the fly system.108 This finding is supported by a mild Notch phenotype observed in β4-galactosyl transferase-1 knockout mice.109 In addition to O-fucosylation, an Oglucose-containing trisacchride (Xylα1-3Xylα1-3Glcβ1-O-Serine) also seems to modulate Notch signaling, though the exact mechanism is not clear.110 The role of Notch signaling in neuronal development is well established. An elegant study by Bejjani and Hammarlund, using single-neuron analysis, showed that Notch/lin-12 inhibits regeneration of mature neurons after injury in C. elegans. The Notch signaling not only affects growth cone initiation after injury but also has profound effects on the regeneration,
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POLYFUCOSYLATED N-GLYCANS IN HYDRA REGENERATION The freshwater polyp Hydra has a remarkable capacity to regenerate from amputated body parts and cell aggregates.94,95 Because of this function, Hydra is used as a model system to study stem cell biology and regeneration. Recent publication from our group showed that Hydra magnipapillata express unique polyfucosylated, LacdiNAc antennary N- and Oglycans.96 Inhibition of the binding of polyfucosylated glycans with their endogenous lectins using Lotus tetragonolobus agglutinin (LTA) abolishes the regeneration of head and foot (Figure 3). A similar phenotype was also observed when the body columns were treated with global metabolic inhibitor of fucosylation, suggesting the role of polyfucosylated glycans in Hydra regeneration. Furthermore, a probable receptor for polyfucosylated glycans has been identified through pull-down experiment and seems to be expressed only in the endodermal cells of Hydra (unpublished results). These results suggest involvement of a glycan-receptor-mediated signaling mechanism in Hydra regeneration.
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GLYCOSAMINOGLYCANS AND LIMB REGENERATION The limb regeneration in adult Urodeles (newts and salamanders) is one of the thoroughly studied fields that provide insights into post-traumatic repair of complex tissue 100
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limiting both morphological and functional recovery after nerve injury.111 Notch signaling has been shown to be essential for maintenance of blastema cells in a proliferative undifferentiated state during Xenopus larval tail112 and zebrafish (Danio rerio) fin regeneration.113 Results from Notch inhibitor studies suggest that Notch pathway activity is induced in regenerating fins predominately in the blastema at the onset of regenerative outgrowth. In contrast to Notch loss of function, which completely blocked growth, NICD overexpression did allow for some increase in fin length; however, this progressively slowed over the course of the experiment. Finally, Notch signaling seems to suppress osteoblast differentiation. Notch signaling has also been implicated in zebrafish heart regeneration.114 Using a combination of fluorescent reporter trans-genes, genetic fate-mapping strategies, and a ventriclespecific genetic ablation system, Zhang et al. have discovered that differentiated atrial cardiomyocytes can trans-differentiate into ventricular ardiomyocytes to contribute to zebrafish cardiac ventricular regeneration. Notch signaling gets activated in the atrial endocardium following ventricular ablation, and Notch signaling inhibition blocked the atrial-to-ventricular trans-differentiation and cardiac regeneration.
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REFERENCES
(1) Sanchez Alvarado, A. (2000) Regeneration in the metazoans: why does it happen? Bioessays 22, 578−590. (2) Morgan, T. H. (1901) Regeneration and Liability to Injury. Science 14, 235−248. (3) Michalopoulos, G. K., and DeFrances, M. C. (1997) Liver regeneration. Science 276, 60−66. (4) Holstein, T. W., Hobmayer, E., and Technau, U. (2003) Cnidarians: an evolutionarily conserved model system for regeneration? Dev. Dyn. 226, 257−267. (5) Goss, R. J. (1969) Principles of Regeneration, Academic Press, New York. (6) Baguna, J., Salo, E., and Auladell, C. (1989) Regeneration and pattern-formation in planarians 0.3. Evidence that neoblasts are totipotent stem-cells and the source of blastema cells. Development 107, 77−86. (7) Bosch, T. C. G., Anton-Erxleben, F., Hemmrich, G., and Khalturin, K. (2010) The Hydra polyp: Nothing but an active stem cell community. Dev., Growth Differ. 52, 15−25. (8) Schulman, I. H., and Hare, J. M. (2012) Key developments in stem cell therapy in cardiology. Regener. Med. 7, 17−24. (9) Clements, W. K., and Traver, D. (2013) Signalling pathways that control vertebrate haematopoietic stem cell specification. Nat. Rev. Immunol. 13, 336−348. (10) Takahashi, K., and Yamanaka, S. (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663−676. (11) Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861− 872. (12) Hou, P., Li, Y., Zhang, X., Liu, C., Guan, J., Li, H., Zhao, T., Ye, J., Yang, W., Liu, K., Ge, J., Xu, J., Zhang, Q., Zhao, Y., and Deng, H. (2013) Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science 341, 651−654. (13) Reddien, P. W., and Sanchez Alvarado, A. (2004) Fundamentals of planarian regeneration. Annu. Rev. Cell Dev. Biol. 20, 725−757. (14) Lerch, J. K., Bixby, J. L., and Lemmon, V. P. (2012) Isoform diversity and its importance for axon regeneration. Neuropathology 32, 420−431. (15) Liu, K., Tedeschi, A., Park, K. K., and He, Z. (2011) Neuronal intrinsic mechanisms of axon regeneration. Annu. Rev. Neurosci. 34, 131−152. (16) Latif, S., Masino, A., and Garry, D. J. (2006) Transcriptional pathways direct cardiac development and regeneration. Trends Cardiovasc. Med. 16, 234−240. (17) Porrello, E. R. (2013) microRNAs in cardiac development and regeneration. Clin. Sci. (London) 125, 151−166. (18) Haltiwanger, R. S., and Lowe, J. B. (2004) Role of glycosylation in development. Annu. Rev. Biochem. 73, 491−537. (19) Ohtsubo, K., and Marth, J. D. (2006) Glycosylation in cellular mechanisms of health and disease. Cell 126, 855−867.
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FUTURE DIRECTIONS Studies involving glycans in regeneration is limited as compared to gene and transcriptional regulation. So, there is an urgent need to encourage research on glycans in regeneration along with other ‘omics’ studies. As evident from this discussion, the role of glycans in the regeneration of neurons is by far the best studied system. However, there is not a single report on the effect of PSA, CSPGs, and glycolipids in axon regeneration. Future studies of regeneration with systems glycan analysis and their regulation would provide comprehensive data that may be directly useful for medical intervention and therapeutics, especially, as stem cell replacement therapy and regenerative medicine is believed to be the future of medicine.
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Mucins: a family of heavily glycosylated high molecular weight proteins with O-GalNAcylated serine and/or threonine repeating sequences Progenitor cells: multipotent stem cell populations which are developmentally committed to become one or more cell types and are undifferentiated or immature compared to fully differentiated tissue cells Dedifferentiation: complex cellular process by which terminally differentiated cells reverts back to earlier developmental stage Plasticity: the ability of a cell or tissue to undergo biochemical structural or physiological change. In different circumstances PSA can affect many types of plasticity in both the developing and adult nervous system
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The author declares no competing financial interest.
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ACKNOWLEDGMENTS The author thanks P. Sai Sudha, Instem for critically reviewing this article and S. Ramaswamy and T. Saiyed, CCAMP for their support and comments.
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KEYWORDS Stereochemistry: the study of the static and dynamic aspects of the three-dimensional shapes of molecules Reaggregation: spontaneous aggregation of separate cells into a cell mass which can develop into a fully grown organism as in Hydra. Extracellular matrix: an extracellular part of tissue containing a complex mixture of secreted proteins such as collagen and laminin polysaccharides and growth factors Polysialyltransferase: a Golgi enzyme that adds α2-8 sialic acid residues to a terminal sialic acid on N-glycan; they can extend up to 300 sialic-acids-containing linear polymers per N-glycan 101
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