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: An unexpected finding in our studies was that HSPG core proteins act in several parallel genetic pathways and redundantly to mediate kal-1-dependent branching. Because kal-1 requires a distinct set of HS modifications for branching in AIY (6-O-, 2-O-, and 3-O-sulfation and C-5-epimerization) (Bülow and Hobert 2004; Tecle et al. 2013), one possibility would be that HSPGs from all surrounding tissues carry the same HS modification patterns (required for kal-1-dependent branching) and, possibly, that a critical amount is required that one tissue alone would not be able to supply. However, we consider this scenario less likely for the following reasons. First, expression analyses of genes encoding HS modifying enzymes indicate that these genes are differentially expressed in different tissues (Bülow and Hobert 2004), rendering it highly unlikely that HSPGs of different cellular origin bear the same HS modification patterns. Second, direct visualization of defined HS modification patterns in live animals display strikingly specific cellular expression patterns in C. elegans (Attreed et al. 2012). Thus, based on the data we present here and known expression data for the involved genes, we propose the following model (Figure 6A). UNC-52/perlecan is secreted by the muscle and localized to the extracellular matrix between the hypodermis and the muscle (Moerman et al. 1996). Therefore, the sulfated HS epitope that contains 2-O-, 3-O-, and 6-O-sulfation and that is produced by the muscle could be carried by UNC-52/perlecan. Second, sdn-1/syndecan has been shown to rescue its mutant phenotypes when expressed pan-neuronally (Rhiner et al. 2005), and much of the HS in nematodes is associated with SDN-1/syndecan in the nervous system (Minniti et al. 2004). Thus, the highly sulfated HS epitope that contains C-5 epimerized and 6-O- and 3-O sulfated HS and is produced by neurons is most likely carried by SDN-1/syndecan. Third, lon-2/glypican has been shown to act in the hypodermis to mediate migration of HSN motor neurons in a HS-dependent manner (Pedersen et al. 2013). Therefore, the less sulfated HS epitope that is dependent on HS 6-O-sulfation and partially on HS- 2-O-sulfation and is produced by the hypodermis may be carried by LON-2/glypican.
Affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, 10461.