Identification of a signaling pathway activated specifically in the somatodendritic compartment by a heparan sulfate that regulates dendrite growth.

In two earlier reports we demonstrated that natural heparan sulfate, but not dermatan or chondroitin sulfate glycosaminoglycans, stimulate axonal elongation and inhibit dendrite growth in vitro (Lafont et al., 1992). The latter specific effect on dendrite elongation was reproduced by chemically synthesized heparan sulfates and by SR 80037A, a purified sulfated and hexanoylated heparin fragment (Lafont et al., 1994). Adding radioactive SR 80037A to purified neurons demonstrated the existence, at the neuronal surface, of heparan sulfate-specific and saturable binding sites, suggesting that SR 80037A activates specific signal transduction pathways. In the present study, using rat or mouse neurons from the embryonic cortex, we show that SR 80037A signaling involves one or several G-coupled receptor or receptors, small GTPases rhoA and/or rhoC, and one or several PKCs. We also demonstrate that the rapid soma rounding elicited by SR 80037A does not require protein synthesis but that the long-term effect on dendrite initiation requires protein synthesis in a short period after the addition of the heparan sulfate. Finally, by preparing membranes from the somatodendritic or axonal compartments we demonstrate that the identified signaling pathway is activated by SR 80037A primarily in the somatodendritic compartment and is not sensitive to the addition of a dermatan sulfate glycosaminoglycan that does not induce the axonal phenotype by impairing dendrite initiation and elongation.