Given their ubiquitous presence and varied complexity on all cell surfaces, it is not surprising that glycans have many diverse roles in various physiological systems of complex multicellular organisms (see Chapter 6). This brief chapter serves as a guide to the rest of the book from the perspective of a reader interested in specific physiological systems, and it provides examples of the roles of glycans in development and systemic physiology. The focus of this chapter is on vertebrate systems. Pathological processes involving glycans are mainly discussed in other chapters. However, because they often provide clues to normal functions, some examples are mentioned here.

REPRODUCTIVE BIOLOGY

Abundant evidence indicates that both male and female reproductive processes are affected by glycans and glycan-binding proteins. Fertilization begins with contact between swimming sperm and the extracellular matrix of the egg and it ends with the fusion of sperm and egg haploid pronuclei, which restores the diploid genome and creates the zygote. Fertilization has been studied extensively in sea urchins, fish, frogs, and mammals. Evidence for the involvement of glycans in many steps is compelling. Sea urchin and mouse fertilization are the best-characterized systems, and these are covered in more detail in Chapter 25. Glycans also have many roles in other aspects of reproduction. Examples include the significance of glycan recognition in sperm interactions with the lining of the fallopian tube and functions of glycans in the process of implantation of the early embryo. Interactions between oocytes and cumulus cells involving hyaluronan in the ovary are discussed in Chapter 15. Genetic modifications of glycosylation in mice have also revealed examples of male infertility caused by glycan structural perturbations (see Chapter 13).

EMBRYOLOGY AND DEVELOPMENT

As a general rule, genetic modifications that affect early stages in the assembly or initiation of a major glycan pathway result in embryonic lethality. Indeed, with the exception of the mucin O-glycan pathway (where complete elimination is difficult because of multiple polypeptide:O-GalNAc transferase isoforms), gene-knockout experiments in mice have demonstrated a critical role in embryogenesis for all other major classes of glycans, as well as for certain classes of monosaccharides such as sialic acids. As might be expected, the resulting embryonic phenotypes are complex, and no single mechanism can easily explain the causes of lethality. For example, disruption of protein O-fucosylation causes a defect in Notch receptors that results in a severe embryonic phenotype (see Chapter 12). Major modifications of glycosaminoglycans also cause developmental abnormalities, most likely because of their roles in modulating growth factor function and their proposed roles in setting up morphogen gradients (see Chapter 16). However, mutations in proteoglycan core proteins can have variable effects, usually in a tissue-specific manner (see Chapters 16, 23, and 25).

In contrast to the effects of eliminating entire glycan classes, specific modifications of terminal structures on glycans (such as specific sialic acid linkages) usually do not have dramatic effects in development, allowing the production of viable offspring with varying and usually limited abnormalities. Such mutants are more likely to show specific defects in restricted cell types (see below).

MUSCULOSKELETAL BIOLOGY

Glycans appear to have a critical role in the interactions of extracellular matrix molecules like laminin with glycan chains on α-dystroglycan, which is a key component of muscle. Multiple defects in the pathway for assembly of these O-mannose-linked glycans are known to be associated with muscular dystrophies of various kinds, both in humans and in mice (see Chapter 42). Glycan-related interactions may also have important roles in the functioning of the muscle–nerve junctions, including the clustering of acetylcholine receptors. Other evidence suggests that sialic acids may have roles in modulating calcium fluxes in skeletal and cardiac muscle cells. The process of formation and ossification of cartilage into bone intimately involves a variety of glycosaminoglycans, including hyaluronan, heparan and chondroitin sulfate, and keratan sulfate (see Chapters 15 and 16).

CARDIOVASCULAR PHYSIOLOGY

Gene knockouts of hyaluronan synthase indicate that hyaluronan has a critical role in the development of the heart (see Chapter 15). There is considerable evidence that glycosaminoglycans have a role in modulating angiogenesis, partly by virtue of their ability to bind a variety of growth factors (most notably vascular endothelial growth factor and fibroblast growth factor) (see Chapter 16). The high density of sialic acids at the luminal surface of endothelial cells and the presence of glycosaminoglycans within the basement membrane underlying the endothelial cells are thought to contribute to the structural integrity of the vessel wall. As mentioned above with skeletal muscle, evidence suggests that sialic acids have as yet unclear roles in modulating calcium fluxes in cardiac muscle cells.

AIRWAY AND PULMONARY PHYSIOLOGY

As with all organs that contain lumens, the lining epithelia of the upper and lower airways are coated with a dense and complex layer of glycans, both in the form of structural glycoproteins and glycolipids of the luminal border of the epithelial cells and also as secreted soluble mucin molecules. Both membrane-bound and soluble glycoconjugates have roles in the effective functioning of the airways, in hydration of the surfaces, and in protection against external agents, both physical and microbial. Embryonic stem cells that lack complex N-glycans do not form part of the organized layer of bronchial epithelium. Normal N-glycans are also important for healthy lung function, because mice lacking the core α1–6 fucose of N-glycans develop emphysema-like symptoms due to overexpression of matrix metalloproteinases that degrade the lung tissue. This is apparently caused by a misregulation of the transforming growth factor-β1 signaling pathway, most likely through its misglycosylated receptor.

ENDOCRINOLOGY

There is abundant evidence that O-GlcNAc has a role in modulating the actions of insulin and in explaining some of the effects of hyperglycemia on a variety of systems (see Chapter 18). In the thyroid gland, the glycosylation of thyroglobulin is thought to be involved in the targeting of the molecule for its eventual degradation, which is required for the generation of thyroid hormones. One possible mechanism is the recognition of mannose 6-phosphate residues on the thyroglobulin N-glycans by lysosomal receptors (see Chapter 30). Pituitary glycoprotein hormones are known to carry unusual sulfated N-glycans (see Chapters 13 and 28), which appear to be involved in the rapid clearance of these hormones from the blood stream. This pharmacodynamic effect of sulfated N-glycans optimizes the response of the target organs (i.e., the gonads) to these hormones. Mice deficient in their ability to make triantennary N-glycans develop the characteristics of type II diabetes, especially when they are fed a high-fat diet. This appears to result from altered glycosylation of the GLUT2 glucose transporter in the pancreatic islet cells. The improper glycosylation leads to accelerated endocytosis of the transporter, leaving an insufficient amount on the surface to perform its critical role in the ultimate action of insulin.

GASTROENTEROLOGY

The comments above regarding the lining of the airways also apply to the luminal lining of the gastrointestinal system. Given the microbial contents of the gut, the importance of glycans in physical protection against luminal contents is likely even greater in this instance. The glycosphingolipids of gastrointestinal epithelial cells are highly concentrated at the outer leaflet of the apical domain, such that they may even outnumber phospholipids as the dominant component of this leaflet. There is also abundant evidence for the involvement of glycans in the interactions of pathogens and symbionts with the gastrointestinal epithelium, ranging from interaction of Helicobacter species with the stomach mucosa to the symbiotic relationships of anaerobic bacteria in the colon, which selectively bind to Galα1-4Gal sequences found in the internal regions of glycosphingolipids (see Chapters 34 and 39). Also of interest is the fact that Helicobactor pylori infection is rarely found in the duodenum, where certain unusual α1-4GlcNAc-terminated O-linked mucins are expressed. This glycan apparently acts as a natural antibiotic against H. pylori infections by inhibiting the biosynthesis of Glcα-O-cholesterol, a major cell-wall component. There is also evidence for extensive “glycan foraging” by various organisms in the gastrointestinal tract, as part of their complex relationship with the host (see Chapter 34). Heparan sulfate in the basement membrane also serves a critical role as a permeability barrier, preventing protein loss into the gut.

HEPATOLOGY

The great majority of proteins secreted by the liver are heavily glycosylated. Hepatocytes have thus been traditionally an excellent system for studying the organization and function of the Golgi apparatus. Various cell types of the liver also express a variety of receptor systems that mediate clearance, based on recognition of specific glycans on circulating molecules (see Chapters 26, 28, 29, and 31 for examples of liver receptor specificities). These receptor systems appear to cooperate to remove unwanted molecules from the circulation. There is also emerging evidence for a role of glycosaminoglycans in controlling lipoprotein clearance in the liver via sequestration of lipoproteins in the space of Disse, which is located between the fenestrated endothelium and the hepatocytes, and by affecting endocytosis.

NEPHROLOGY

There is extensive evidence that heparan sulfate glycosaminoglycans (see Chapter 15) and sialic acid residues (see Chapter 14) on podocalyxin are involved in assuring the optimal filtering function of the glomerular basement membrane. As with any organ system with hollow cavities, mucin-like molecules and glycosaminoglycans have an important role in providing a barrier function at the luminal surface of the ureter and bladder. Reduced branching of complex N-glycans causes kidney pathology that may result from an autoimmune response.

SKIN BIOLOGY

Glucosylceramide and related glycosphingolipids and adducts appear to have a critical role in maintaining the barrier function of the skin. There is also evidence for a role for dermatan sulfate glycosaminoglycans in maintaining the structure of the dermis and in facilitating wound repair. A lack of O-fucose glycans on Notch receptors results in skin lesions due to changes in hair cell differentiation (see Chapter 12).

ORAL BIOLOGY

Glycosaminoglycans (see Chapters 15 and 16) have a critical role in the development, organization, and structure of both the gums and teeth. Interaction of various oral commensal organisms with the host epithelium can involve recognition of glycans. Mucins produced by the salivary glands may have protective effects in the oral cavity, preventing bacterial biofilm formation on teeth (see Chapters 9 and 39).

HEMATOLOGY

Many aspects of the structure and function of blood components are affected by glycosylation. The trafficking of leukocytes throughout the body is regulated by glycan recognition, particularly with regard to ligands of the selectins (see Chapter 31). Variable glycosylation of red blood cells is responsible for explaining many of the intraspecies blood group differences that affect the practice of blood transfusion (see Chapter 13). There is conflicting evidence about whether or not the half-life of red blood cells in circulation is determined by changes in cell-surface glycans. Nearly all blood proteins are N-glycosylated, which is important for maintaining their stability in the circulation. Patients with impaired N-glycosylation often have insufficient levels of coagulation factors such as antithrombin-III and proteins C and S (see Chapter 42).

IMMUNOLOGY

Terminal components of N- and O-glycans appear to have important roles not only in the trafficking of lymphocytes and other immune cells, but also in their differentiation and/or apoptosis (see Chapter 42). Sialic acid recognition by Siglec adhesion molecules has a role in regulating immune responses (see Chapter 32), and the O-fucose glycans on Notch receptors regulate many cell differentiation processes, including thymic development (see Chapter 12).

NEUROBIOLOGY

The unusual polysialic acid structure attached to the neural cell-adhesion molecule appears to modulate the plasticity of the nervous system with respect to neural changes during embryogenesis in adult life (see Chapter 14). Neural cells are also highly enriched in sialic-acid-containing glycolipids (gangliosides), and alterations in these glycans affect neurological function (see Chapter 10). There are two instances wherein specific glycans appear to inhibit nerve regeneration after injury. In the first, recognition of certain sialylated glycolipids by myelin-associated glycoprotein appears to send a negative signal against neuronal sprouting following injury (see Chapter 32). Similar inhibitory effects appear to be mediated by the glycosaminoglycan chondroitin sulfate (see Chapter 16). In both instances, targeted degradation of the glycan in vivo (by local injection of sialidase or chondroitinase) can stimulate growth and repair, supporting the hypothesis that these glycans normally act to block regeneration. On the basis of genetic defects induced in animals, there is also evidence that complex N-glycans and glycosaminoglycans have critical roles in the development and organization of the nervous system (see Chapters 8 and 16). Indirect evidence indicates a role for fucosylated N-glycans in modulating various aspects of neural development and function (see Chapter 42).

FURTHER READING

1. Varki A. Biological roles of oligosaccharides: All of the theories are correct. Glycobiology. 1993;3:97–130. [PMC free article: PMC7108619] [PubMed: 8490246]
2. Mahley RW, Ji ZS. Remnant lipoprotein metabolism: Key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. J Lipid Res. 1999;40:1–16. [PubMed: 9869645]
3. Mengerink KJ, Vacquier VD. Glycobiology of sperm–egg interactions in deuterostomes. Glycobiology. 2001;11:37R–43R. [PubMed: 11358873]
4. Yamaguchi Y. Glycobiology of the synapse: The role of glycans in the formation, maturation, and modulation of synapses. Biochim. Biophys. Acta. 2002;1573:369–376. [PubMed: 12417420]
5. Diekman AB. Glycoconjugates in sperm function and gamete interactions: How much sugar does it take to sweet-talk the egg. Cell Mol Life Sci. 2003;60:298–308. [PubMed: 12678495]
6. Haines N, Irvine KD. Glycosylation regulates Notch signaling. Natl Rev Mol Cell Biol. 2003;4:786–797. [PubMed: 14570055]
7. Furukawa K, Tokuda N, Okuda T, Tajima O, Furukawa K. Glycosphingolipids in engineered mice: Insights into function. Semin Cell Dev Biol. 2004;15:389–396. [PubMed: 15207829]
8. Haltiwanger RS, Lowe JB. Role of glycosylation in development. Annu Rev Biochem. 2004;73:491–537. [PubMed: 15189151]
9. Sonnenburg JL, Xu J, Leip DD, Chen CH, Westover BP, Weatherford J, Buhler JD, Gordon JI. Glycan foraging in vivo by an intestine-adapted bacterial symbiont. Science. 2005;307:1955–1959. [PubMed: 15790854]
10. Stanley P. Regulation of Notch signaling by glycosylation. Curr Opin Struct Biol. 2007;17:530–535. [PMC free article: PMC2141538] [PubMed: 17964136]