Syndecan Regulates Cellular Morphogenesis in Cooperation with the Netrin Guidance Pathway and Rho-family GTPases

The establishment of complex cell shapes is essential for specific cellular functions, and thus critical in animal development and physiology. Heparan sulfate proteoglycans (HSPGs) are conserved glycoproteins that regulate interactions between extracellular signals and their receptors, to orchestrate morphogenetic events and elicit cellular responses. Although HSPG-regulated pathways have been implicated in regulating the guidance of neuronal migrations, whether HSPGs regulate earlier aspects of cellular development that dictate cell shape remains unknown. HSPGs consist of a protein core (e.g., Syndecan, Perlecan, Glypican, etc.) with attached heparan sulfate (HS) glycosaminoglycan chains, which are synthesized by glycosyltransferases of the exostosin family. Using mutations in the two C. elegans HS glycosyltransferases genes, rib-1 and rib-2, we reveal that HSPGs control the number of cellular projections in the epithelial excretory canal cell, which can form more than its normal four canals in these mutants. We identify SDN-1/Syndecan as the key HSPG that regulates the number of excretory canal cell projections in a cell-autonomous manner. We also find that Syndecan and guidance receptors for Netrin function in the same pathway to restrict the number of cellular projections. Furthermore, we show that the formation of extra projections in the absence of Syndecan requires the conserved Rho-family GTPases CED-10/Rac and MIG-2/RhoG. Our findings not only contribute to understanding the roles of conserved HSPGs in cellular morphogenetic events, but also reveal the existence of an HSPG-regulated system operating to guarantee that a precise number of cellular projections is established during cell development. Given the evolutionary conservation of developmental mechanisms and the molecules implicated, this work provides information relevant to understanding the cellular and molecular bases of the development of precise cellular morphologies in varied cell types across animals.