Glycans have numerous physiological functions. This brief chapter will guide readers to focus on glycans in normal organ system functions, mostly in vertebrates. Pathological aspects of glycan biosynthesis and degradation are discussed elsewhere. Given the breadth of physiological functions of glycans, the individual sections indicate just a few representative examples, and listings are necessarily incomplete.

REPRODUCTIVE BIOLOGY

Glycans and glycan-binding proteins are important for both male and female reproductive function. Studies in sea urchins, fish, frogs, and mammals have shown that glycans are involved in many specific steps during fertilization (Chapter 27). Glycan recognition occurs during sperm interactions with reproductive tract mucins of animals with internal fertilization mechanisms, in the lining of the fallopian tubes, and during implantation of the early embryo. Glycosylation-deficient male mice are sometimes infertile or subfertile. Following birth in mammals, lactation generates a rich mixture of biologically important glycoconjugates, especially the milk oligosaccharides, a unique class of free secreted glycans that vary greatly in complexity and diversity among species (Chapter 14).

EMBRYOLOGY AND DEVELOPMENT

Genetic modifications that eliminate initial steps of major glycan synthetic pathways and of some monosaccharide biosynthetic pathways generally result in embryonic lethality, in most but not all taxa. One exception is the mucin O-GalNAc glycan, as there are 20 different polypeptide:O-GalNAc transferases (Chapter 10). It is not yet clear if any members of this gene family are nonredundant in mammalian development; however, in Drosophila, elimination of certain O-GalNAc transferases is lethal. Overall, the embryonic phenotypes of lethal defects in glycan biosynthesis are complex and cannot be explained by a single mechanism. For example, disruption of protein O-fucosylation causes a defect in global Notch receptor signaling leading to embryonic lethality (Chapter 13). Conversely, loss of modifications of terminal structures on glycans usually does not have an embryonic lethal outcome, but viable offspring show more specific defects in restricted cell types. Elimination of glycosaminoglycans also causes developmental abnormalities, most likely because of their roles in modulating growth factor function and in setting up morphogen gradients (Chapter 17). Although the elimination of glycosaminoglycans causes systemic developmental abnormalities, elimination of some proteoglycan core proteins that carry these glycans can have tissue-specific consequences (Chapters 17, 25, and 26).

HEMATOLOGY

Glycans affect the functions of all classes of blood cells. Many blood group antigens on erythrocytes are glycans, and successful blood transfusion requires compatibility of these antigens between donor and recipient (Chapter 14). Selectin ligands and their receptors (Chapter 34) play critical roles in trafficking of leukocytes from the bloodstream into tissues. Nearly all proteins in plasma are N-glycosylated, a feature that is critical for maintaining stability in the circulation, as well as optimal function. Thus, patients with defects in N-glycosylation often have insufficient levels of coagulation factors such as antithrombin III and proteins C and S, because of accelerated clearance of these proteins from the circulation (Chapter 45). The O-fucose glycans on Notch receptors regulate hematopoiesis and the hematopoietic stem cell niche (Chapter 13).

IMMUNOLOGY

In addition to controlling tissue trafficking of lymphocytes and monocytes, N- and O-glycans control differentiation, adhesion, and survival of these cells (Chapters 36 and 45). Signaling in leukocytes is also regulated by Siglecs, which recognize sialic acid–containing ligands as “self-associated molecular patterns” (SAMPs, Chapter 35), and O-fucose glycans on Notch receptors regulate many cell differentiation processes, including development of T cells in the thymus (Chapter 13). Galectins (Chapter 36) play key roles in immune cell activation and function, as do C-type lectins on antigen presenting cells (Chapter 34). Glycans are critical components of many antigens and may determine how epitopes are presented (e.g., presentation of glycolipid antigens by CD1a-positive lymphocytes). There is a large and complex literature about the multiple roles of N-glycans on the IgG Fc domain, in modulating antibody effector functions.

CARDIOVASCULAR PHYSIOLOGY

Hyaluronan has a critical role in the development of the heart (Chapter 16), and glycosaminoglycans modulate angiogenesis, in part because they bind growth factors such as vascular endothelial growth factor and fibroblast growth factor (Chapter 17). The structural integrity of the walls of blood vessels is thought to depend on glycans, including a high density of sialic acids at the luminal surface of endothelial cells, as well as glycosaminoglycans within the basement membrane underlying the endothelial cells. Cardiac muscle integrity and optimal physiology depend on various glycans.

AIRWAY AND PULMONARY PHYSIOLOGY

Epithelial cells in the upper and lower airways synthesize a dense and complex array of glycans on their luminal surface. Structural glycoproteins, glycolipids, and secreted mucin molecules form barriers that maintain hydration of the epithelial surfaces, and protect against physical and microbial invasion. Embryonic stem cells lacking complex N-glycans cannot properly organize the bronchial epithelium. N-glycans are also important for healthy lung function, as mice lacking the core α1-6 fucose of N-glycans develop emphysema-like symptoms caused by overexpression of matrix metalloproteinases that degrade the lung tissue; this may result from aberrant transforming growth factor-β1 signaling through its misglycosylated receptor. Gene knockouts of individual mucin polypeptides reveal diverse overlapping functions. Mice lacking O-fucose glycans in the lung do not generate secretory cells necessary for airway development.

ENDOCRINOLOGY

O-GlcNAc on proteins of the nucleus and cytoplasm modulates insulin action, and aberrant O-GlcNAcylation is involved in many of the effects of hyperglycemia (Chapter 19). N-glycans also play a role in type II diabetes, as mice that cannot synthesize triantennary N-glycans develop diabetes when fed a high-fat diet. This deficiency alters the single N-glycan on the GLUT2 glucose transporter on pancreatic islet cells, leading to accelerated endocytosis, depletion from the cell surface, and poor response to insulin. N-glycans are critical for the production of functional thyroid hormones, as targeting and uptake of thyroglobulin that is converted to T3 and T4 in the thyroid gland may require Man-6-P-containing glycans on thyroglobulin (Chapter 33). The plasma half-life of several pituitary glycoprotein hormones is regulated by the presence of N-glycans that contain an unusual sulfated GalNAc (Chapters 14 and 31), which controls hormone clearance in the liver.

ORAL BIOLOGY

Glycosaminoglycans (Chapters 16 and 17) play critical roles in the development, organization, and structure of both the gums and teeth. Interactions of various oral commensal organisms with the host epithelium and with one another often involve glycan recognition. Mucins produced by the salivary glands may have protective effects in the oral cavity, preventing bacterial biofilm formation on teeth (Chapters 10 and 42). However, mucin sialoglycans also provide binding sites for tooth cavity–facilitating bacteria. Glycoproteomic analysis of saliva may be useful to identify disease biomarkers.

GASTROENTEROLOGY

The gastrointestinal system has to live in equilibrium with the microbial contents of the gut. Extensive “glycan foraging” by various organisms occurs in the gastrointestinal tract, as part of the complex relationship of the microbiome with the host (Chapter 37). Glycans are critical for providing physical protection against luminal contents of the gut and organize the mucin barrier that lines the gut. Glycans on the epithelial surface interact with both symbionts and pathogens, ranging from Helicobacter species in the stomach to anaerobic bacteria in the colon (Chapters 37 and 42). Helicobactor pylori infection is rarely found in the duodenum, where unusual GlcNAcα1-4-terminated O-linked mucins are expressed; this glycan apparently acts as an antimicrobial to control H. pylori infection. Heparan sulfate in the intestinal basement membrane also serves a crucial role as a permeability barrier, preventing protein loss from the plasma into the gut. O-fucose glycans in the small intestine regulate the balance of secretory and goblet cells necessary for intestinal development.

HEPATOLOGY

The liver synthesizes a large fraction of plasma proteins, and nearly all proteins secreted by the liver are heavily N-glycosylated, making hepatocytes a traditional cell type for studying the organization and function of the Golgi apparatus. Both hepatocytes and Kupffer cells in the liver have specific glycan-based recognition systems to clear unwanted circulating molecules (see Chapters 28, 31, 32, and 34 for examples of liver receptor specificities). Heparan sulfate proteoglycans in the space of Disse between fenestrated endothelium and hepatocytes bind lipoproteins and aid in their clearance.

NEPHROLOGY

Heparan sulfate glycosaminoglycans (Chapter 17) and sialic acid residues (Chapter 15) on podocalyxin are involved in assuring the optimal filtering function of the glomerular basement membrane. In addition, reduced branching of complex N-glycans causes kidney pathology that may result from an autoimmune response. As in the pulmonary and gastrointestinal tracts, mucins with O-GalNAc glycans (Chapter 10) and proteoglycans with glycosaminoglycans provide a barrier function at the luminal surfaces of the ureters and bladder.

SKIN BIOLOGY

Glucosylceramide and related glycosphingolipids appear to have a critical role in maintaining the barrier function of the skin. Dermatan sulfate helps maintain the structure of the dermis and participates in wound repair.

MUSCULOSKELETAL BIOLOGY

Proper adhesion of skeletal muscle to extracellular matrix laminin requires unique O-mannose glycans on the sarcolemmal glycoprotein α-dystroglycan (Chapter 27). Various defects in this pathway cause mild to severe muscular dystrophies in both humans and mice (Chapter 45). Glycan-related interactions can promote clustering of acetylcholine receptors at neuromuscular junctions. Sialic acid–containing glycans are found on many ion transport proteins, and loss of these glycans impairs functions such as modulation of calcium fluxes into skeletal muscle cells. Normal formation and ossification of cartilage into bone requires many glycosaminoglycans, including hyaluronan and heparan, chondroitin, and keratan sulfates (Chapters 16 and 17).

NEUROBIOLOGY

The central nervous system has the highest amount and concentration of sialic acid–containing glycolipids (gangliosides; Chapter 11), and alterations in these glycans affect neurological function. O-GlcNAcylation in specific cells of the brain sense nutrients and regulate satiety. The unusual polysialic acid chains on NCAM (neural cell adhesion molecule) differentially modulate the plasticity of the nervous system during embryogenesis (Chapter 15). The dystroglycanopathies mentioned above also typically have cognitive and/or neurologic defects in addition to muscle dysfunction (Chapter 45). There are additional instances wherein specific glycans appear to inhibit nerve regeneration after injury. Recognition of certain sialylated glycolipids by myelin-associated glycoprotein appears to send a negative signal to restrain neuronal sprouting following injury (Chapter 35), and similar inhibitory effects may be mediated by the glycosaminoglycan chondroitin sulfate (Chapter 17). In both instances, targeted degradation of the glycan in vivo (by local injection of sialidase or chondroitinase, respectively) can stimulate neuronal growth and repair, supporting the hypothesis that these glycans normally act to block neuronal regeneration. Genetic defects in mutant mice provide evidence that complex N-glycans and glycosaminoglycans have critical roles in the development and organization of the nervous system (Chapters 9 and 17). Fucosylated N-glycans appear to play a role in modulating various aspects of neural development and function. The great majority of patients with inherited glycosylation disorders also have cognitive and/or neurological abnormalities, but specific mechanisms are mostly unknown (Chapter 45).

ACKNOWLEDGMENTS

The authors acknowledge contributions to previous versions of this chapter by Victor Vacquier and appreciate helpful comments and suggestions from Aime Lopez Aguilar, Daniela Janevska Carroll, Ryan Porell, and Eathen Ryan.

FURTHER READING

A wide range of topics are covered here and only a few references can be given. Please also see the citations at the ends of individual chapters referred to above.

• Varki A. 2008. Sialic acids in human health and disease. Trends Mol Med 14: 351–360. [PMC free article: PMC2553044] [PubMed: 18606570]
• Stanley P, Okajima T. 2010. Roles of glycosylation in Notch signaling. Curr Top Dev Biol 92: 131–164. [PubMed: 20816394]
• Ohtsubo K, Chen MZ, Olefsky JM, Marth JD. 2011. Pathway to diabetes through attenuation of pancreatic β cell glycosylation and glucose transport. Nat Med 17: 1067–1075. [PMC free article: PMC3888087] [PubMed: 21841783]
• Bennett EP, Mandel U, Clausen H, Gerken TA, Fritz TA, Tabak LA. 2012. Control of mucin-type O-glycosylation: A classification of the polypeptide GalNAc-transferase gene family. Glycobiology 22: 736–756. [PMC free article: PMC3409716] [PubMed: 22183981]
• Hansson GC. 2012. Role of mucus layers in gut infection and inflammation. Curr Opin Microbiol 15: 57–62. [PMC free article: PMC3716454] [PubMed: 22177113]
• Live D, Wells L, Boons GJ. 2013. Dissecting the molecular basis of the role of the O-mannosylation pathway in disease: α-dystroglycan and forms of muscular dystrophy. Chembiochem 14: 2392–2402. [PMC free article: PMC3938021] [PubMed: 24318691]
• Marcobal A, Southwick AM, Earle KA, Sonnenburg JL. 2013. A refined palate: Bacterial consumption of host glycans in the gut. Glycobiology 23: 1038–1046. [PMC free article: PMC3724412] [PubMed: 23720460]
• Hardivillé S, Hart GW. 2014. Nutrient regulation of signaling, transcription, and cell physiology by O-GlcNAcylation. Cell Metab 20: 208–213. [PMC free article: PMC4159757] [PubMed: 25100062]
• Macauley MS, Crocker PR, Paulson JC. 2014. Siglec-mediated regulation of immune cell function in disease. Nat Rev Immunol 14: 653–666. [PMC free article: PMC4191907] [PubMed: 25234143]
• Mi Y, Lin A, Fiete D, Steirer L, Baenziger JU. 2014. Modulation of mannose and asialoglycoprotein receptor expression determines glycoprotein hormone half-life at critical points in the reproductive cycle. J Biol Chem 289: 12157–12167. [PMC free article: PMC4002119] [PubMed: 24619407]
• Whitsett JA, Alenghat T. 2015. Respiratory epithelial cells orchestrate pulmonary innate immunity. Nat Immunol 16: 27–35. [PMC free article: PMC4318521] [PubMed: 25521682]
• Stanley P. 2017. What have we learned from glycosyltransferase knockouts in mice? J Mol Biol 428: 3166–3182. [PMC free article: PMC5532804] [PubMed: 27040397]