Glycosylation in Cellular Mechanisms of Health and Disease

Simple and complex carbohydrates (glycans) have long been known to play major metabolic, structural and physical roles in biological systems. Targeted microbial binding to host glycans has also been studied for decades. But such biological roles can only explain some of the remarkable complexity and organismal diversity of glycans in nature. Reviewing the subject about two decades ago, one could find very few clear-cut instances of glycan-recognition-specific biological roles of glycans that were of intrinsic value to the organism expressing them. In striking contrast there is now a profusion of examples, such that this updated review cannot be comprehensive. Instead, a historical overview is presented, broad principles outlined and a few examples cited, representing diverse types of roles, mediated by various glycan classes, in different evolutionary lineages. What remains unchanged is the fact that while all theories regarding biological roles of glycans are supported by compelling evidence, exceptions to each can be found. In retrospect, this is not surprising. Complex and diverse glycans appear to be ubiquitous to all cells in nature, and essential to all life forms. Thus, >3 billion years of evolution consistently generated organisms that use these molecules for many key biological roles, even while sometimes coopting them for minor functions. In this respect, glycans are no different from other major macromolecular building blocks of life (nucleic acids, proteins and lipids), simply more rapidly evolving and complex. It is time for the diverse functional roles of glycans to be fully incorporated into the mainstream of biological sciences.

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Biological Roles of Glycans

All cells in nature are covered by a dense and complex array of carbohydrates. Given their prominence on cell surfaces, it is not surprising that these glycans mediate and/or modulate many cellular interactions. Proteins that bind sialic acid, a sugar that is found on the surface of the cell and on secreted proteins in vertebrates, are involved in a broad range of biological processes, including intercellular adhesion, signalling and microbial attachment. Studying the roles of such proteins in vertebrates has improved our understanding of normal physiology, disease and human evolution.

Glycan-based interactions involving vertebrate sialic-acid-recognizing proteins

Significant advances have been made in the application of genetics to probe the functions of basement membrane laminins. These studies have shown that different laminin subunits profoundly affect tissue morphogenesis, starting around the time of embryonic implantation and extending through organogenesis and into the postnatal period. Collectively they have revealed common functions that include the induction and maintenance of cell polarity, the establishment of barriers between tissue compartments, the organization of cells into tissues, and the protection of adherent cells from detachment-induced cell death, anoikis. Interpreted in light of what is known about laminin structure and self-assembly and binding activities, these advances have begun to provide insights into mechanisms of action. In this review we focus on the contributions of the laminins in invertebrate and vertebrate tissue morphogenesis.

Laminin functions in tissue morphogenesis

Researchers have long predicted that complex carbohydrates on cell surfaces would play important roles in developmental processes because of the observation that specific carbohydrate structures appear in specific spatial and temporal patterns throughout development. The astounding number and complexity of carbohydrate structures on cell surfaces added support to the concept that glycoconjugates would function in cellular communication during development. Although the structural complexity inherent in glycoconjugates has slowed advances in our understanding of their functions, the complete sequencing of the genomes of organisms classically used in developmental studies (e.g., mice, Drosophila melanogaster, and Caenorhabditis elegans) has led to demonstration of essential functions for a number of glycoconjugates in developmental processes. Here we present a review of recent studies analyzing function of a variety of glycoconjugates (O-fucose, O-mannose, N-glycans, mucin-type O-glycans, proteoglycans, glycosphingolipids), focusing on lessons learned from human disease and genetic studies in mice, D. melanogaster, and C. elegans.

Role of Glycosylation in Development

In the CST, there was a first fixation period of 1 s, followed by a brief presentation (100 ms) of a cue at 208 to the left or to the right The monkey had to maintain his gaze at the fixation spot during a delay period of 1 s The fixation spot then disappeared and the target appeared at the same position as the cue In half of the trials, another spot appeared at the alternative position (distracter) The monkey had to make a saccade to the target position within 500 ms, and was rewarded with a drop of water for a correct saccade After recording neurons in the CST (experiment 2), we re-applied the BST (experiment 1) for at least 80 trials to confirm the reproducibility of neuronal activity Data analysis Pre-target neurons were defined as neurons that showed a statistically reliable increase in the spike count 215 s to 0 s before target onset (‘pre-target window’) as compared with the spike count 2 3s to215 s before target onset All pair-wise comparisons were evaluated by two-tailed t-tests, P , 001 We used the Bonferroni procedure to correct for family-wise error with multiple t-tests To quantify the separation of population distributions from contralateral versus ipsilateral conditions, we calculated the area under the ROC in a sliding window of 200 ms To test the adaptation of saccade latency and pre-target activity to a reversal of position-reward contingency, we compared the second trial after a reversal against the third trial after a reversal (test 1) We also compared the second trial after a reversal against the pooled data from the sixth to twentieth trial (test 2) Both tests consisted of paired twotailed t-tests on the mean data from individual neurons Adaptation was judged complete if there was no significant difference between the measures Tests 1 and 2 produced similar results in all cases For comparison between the two tasks (BST versus CST), we considered the neuronal activity from 2500 to 0 ms before target onset in both tasks, in the computation of absolute firing rates as well as ROC areas

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Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies

We report the familial occurrence of acinic cell carcinoma involving the parotid gland, the first such report of which we are aware. The familial occurrence of any salivary gland neoplasm is rare. Several reports are present in the literature, including pleomorphic adenoma, Warthin tumor, carcinoma of the submandibular gland, and malignant lymphoepithelial lesion. We report the case of a 35-year-old man who underwent excision of a left parotid gland acinic cell carcinoma. Eight years later, his daughter presented at the age of 16 years with a nontender parotid gland mass that was excised and found also to be acinic cell carcinoma. The histologic features of both neoplasms were typical of acinic cell carcinoma. While this may represent a coincidental event, the possibility that this familial occurrence is a manifestation of common genetic or environmental risk cannot be excluded.

James Dollar

Papers

Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies

Familial occurrence of acinic cell carcinoma of the parotid gland.