Diverse roles for glycosaminoglycans in neural patterning

Abstract

The nervous system coordinates the functions of most multicellular organisms and their response to the surrounding environment. Its development involves concerted cellular interactions, including migration, axon guidance, and synapse formation. These processes depend on the molecular constituents and structure of the extracellular matrices (ECM). An essential component of ECMs are proteoglycans, i.e., proteins containing unbranched glycan chains known as glycosaminoglycans (GAGs). A defining characteristic of GAGs is their enormous molecular diversity, created by extensive modifications of the glycans during their biosynthesis. GAGs are widely expressed, and their loss can lead to catastrophic neuronal defects. Despite their importance, we are just beginning to understand the function and mechanisms of GAGs in neuronal development. In this review, we discuss recent evidence suggesting GAGs have specific roles in neuronal patterning and synaptogenesis. We examine the function played by the complex modifications present on GAG glycans and their roles in regulating different aspects of neuronal patterning. Moreover, the review considers the function of proteoglycan core proteins in these processes, stressing their likely role as co-receptors of different signaling pathways in a redundant and context-dependent manner. We conclude by discussing challenges and future directions toward a better understanding of these fascinating molecules during neuronal development.

An Input-Specific Orphan Receptor GPR158-HSPG Interaction Organizes Hippocampal Mossy Fiber-CA3 Synapses

“…Heparan sulfate proteoglycan (HSPG) cell-surface molecules are emerging as regulators of synaptic connectivity across species (Condomitti and de Wit, 2018; Kamimura and Maeda, 2017; Saied-Santiago and Bülow, 2018). Transmembrane and secreted HSPGs comprise a protein core with covalently attached heparan sulfate (HS) polysaccharide chains, which are enzymatically modified and interact with diverse protein ligands (Xu and Esko, 2014).…”

Synaptogenesis Is Modulated by Heparan Sulfate inCaenorhabditis elegans

“…The ECM plays an important role in the development of the nervous system ( Porcionatto 2006 ; Zimmermann and Dours-Zimmermann 2008 ; Myers et al 2011 ). Heparan sulfate (HS) proteoglycans (HSPGs) are components of the ECM that function in several processes such as neurogenesis, cell migration, axon guidance, dendritic branching, and synapse formation ( Bernfield et al 1999 ; Bülow and Hobert 2006 ; Poulain and Yost 2015 ; Saied-Santiago and Bülow 2018 ). HSPGs exist in three different forms: (1) transmembrane proteins such as the syndecans; (2) glycosylphosphatidylinositol (GPI)-anchored proteins such as the glypicans; and (3) secreted forms such as perlecan, agrin, and collagen XVIII ( Bernfield et al 1999 ; Bülow and Hobert 2006 ; Poulain and Yost 2015 ).…”

Structural insight into the binding of human galectins to corneal keratan sulfate, its desulfated form and related saccharides

“…The 50% change in chemical shift occurs at about 2 μM for Gal-3 FL and at about 7 μM for Gal-3 CRD. This affinity/avidity might be altered by changing the status of sulfation, a structural hallmark of glycosaminoglycans that has implications for receptor association 47 – 50 . In principle, two opposite effects may result: enhanced affinity by unmasking the galactose moiety via removal of the 6′-sulfate group and reduced affinity by turning 6-sulfated GlcNAc into unsubstituted GlcNAc.…”