Complex cooperative functions of heparan sulfate proteoglycans shape nervous system development in Caenorhabditis elegans.
Bottom Line: Specifically, lon-2/glypican and unc-52/perlecan act in parallel genetic pathways and display synergistic interactions with sdn-1/syndecan to mediate kal-1 function.Because all of these heparan sulfate core proteins have been shown to act in different tissues, these studies indicate that KAL-1/anosmin-1 requires heparan sulfate with distinct modification patterns of different cellular origin for function.Our results support a model in which a three-dimensional scaffold of heparan sulfate mediates KAL-1/anosmin-1 and intercellular communication through complex and cooperative interactions.
Affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, 10461.Show MeSH
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Mentions: The extracellular matrix (ECM) provides a scaffold for the development and function of tissues and organs. For example, the nervous system makes use of the wide range of signals found in the ECM to mediate processes such as cell migration, axon guidance, and neurite branching (Porcionatto 2006; Zimmermann and Dours-Zimmermann 2008; Myers et al. 2011). Heparan sulfate proteoglycans (HSPGs) are key components of the ECM in mediating nervous system development (Yamaguchi 2001; Bülow and Hobert 2006; Van Vactor et al. 2006). HSPGs exist in membrane-bound forms, such as syndecans and glypicans, or are secreted, such as perlecan, agrin, or collagen XVIII (Figure 1A) (Bernfield et al. 1999). Many but not all functions of HSPGs are mediated by the heparan sulfate (HS) chains attached to their extracellular domain (Häcker et al. 1997). These HS are linear glycosaminoglycan polysaccharides consisting of a characteristic disaccharide repeat of hexuronic acid with glucosamine that can be heavily and diversely modified (Figure 1B). The modifications include sulfations, epimerization, and acetylation of different sugar moieties and are introduced by specific enzymes in the Golgi (Figure 1, B and C) (Lindahl et al. 1998; Esko and Selleck 2002; Lindahl and Li 2009). HS chains are known to function as co-factors and have previously been shown to be part of many signaling pathways (Bülow and Hobert 2006; Bishop et al. 2007), including but not limited to the fibroblast growth factor receptor FGFR, the Slit/Robo ligand/receptor cassette of axon guidance factors, and also the neural cell adhesion molecule KAL1/anosmin-1, which causes hereditary Kallmann syndrome (KS)/idiopathic hypogonadotropic hypogonadism (IHH) (Franco et al. 1991; Legouis et al. 1991).
Affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, 10461.