From Morphogen Gradients to Axon Guidance

Abstract

Heparan sulfate proteoglycans (HSPs) interact with many cell-adhesion proteins and signaling proteins (see the Perspective by Blair ). Two groups investigated HSP interactions with key signaling proteins. Paine-Saunders et al. determined that the bone morphogenic protein (BMP) antagonist Noggin interacted with HSPs and was sequestered at the cell surface when expressed in Chinese hamster ovary cell lines that synthesized HSPs. Surface localization of Noggin appeared to be dependent on heparin sulfate, because Noggin was released from the cell surface by the addition of excess soluble heparin or when expressed in cells with mutations in enzymes essential for heparin sulfate biosynthesis. The heparin-bound Noggin retained biological activity as a BMP antagonist, and the interaction with HSPs may be one mechanism by which gradients of BMP activity are established in vivo. A second group, Ihrie et al. , analyzed how sulfation of specific sites on heparin sulfate contributes to the control of axon guidance in the Xenopus optic pathway. Axon targeting was disrupted when exogenous heparin sulfates were applied or when sulfation of the polysaccharides in the 2- O and 6- O positions was inhibited pharmacologically. Analysis of the expression of the enzymes required for sulfation at the 2- O [heparan sulfate 2- O sulfotransferase (HS2ST)] and 6- O (HS6ST) positions showed broad distribution of the HS2ST modification, but a highly restricted occurrence of HS6ST. Thus, the structure of the HSPs also plays a key role in controlling the interaction between these proteins and those that are important for mediating axon guidance. S. S. Blair, Wnts, signaling and sulfates. Science's STKE (2001), http://stke.sciencemag.org/cgi/content/full/OC_sigtrans;2001/101/pe32 [Abstract] [Full Text] S. Paine-Saunders, B. L. Viviano, A. N. Economides, S. Saunders, Heparan sulfate proteoglycans retain Noggin at the cell surface. J. Biol. Chem. 277 , 2089-2096 (2002). [Abstract] [Full Text] A. Ihrie, E. A. Yates, J. E. Turnbull, C. E. Holt, Specific heparan sulfate structures involved in retinal axon targeting. Development 129 , 61-70 (2002). [Online Journal]