Johnson Karl G, Ghose Aurnab, Epstein Elizabeth, Lincecum John, O'Connor Michael B, Van Vactor David
Harvard Medical School, Department of Cell Biology, Program in Neuroscience, 240 Longwood Avenue, Boston, MA 02115, USA.
Curr Biol. 2004 Mar 23;14(6):499-504. doi: 10.1016/j.cub.2004.02.005.
The presentation of secreted axon guidance factors plays a major role in shaping central nervous system (CNS) connectivity. Recent work suggests that heparan sulfate (HS) regulates guidance factor activity; however, the in vivo axon guidance roles of its carrier proteins (heparan sulfate proteoglycans, or HSPGs) are largely unknown. Here we demonstrate through genetic analysis in vivo that the HSPG Syndecan (Sdc) is critical for the fidelity of Slit repellent signaling at the midline of the Drosophila CNS, consistent with the localization of Sdc to CNS axons. sdc mutants exhibit consistent defects in midline axon guidance, plus potent and specific genetic interactions supporting a model in which HSPGs improve the efficiency of Slit localization and/or signaling. To test this hypothesis, we show that Slit distribution is altered in sdc mutants and that Slit and its receptor bind to Sdc. However, when we compare the function of the transmembrane Sdc to a different class of HSPG that localizes to CNS axons (Dallylike), we find functional redundancy, suggesting that these proteoglycans act as spatially specific carriers of common HS structures that enable growth cones to interact with and perceive Slit as it diffuses away from its source at the CNS midline.
分泌型轴突导向因子的呈现对塑造中枢神经系统（CNS）的连接性起着主要作用。最近的研究表明，硫酸乙酰肝素（HS）调节导向因子的活性；然而，其载体蛋白（硫酸乙酰肝素蛋白聚糖，或HSPG）在体内的轴突导向作用在很大程度上尚不清楚。在这里，我们通过体内遗传分析证明，HSPG Syndecan（Sdc）对于果蝇中枢神经系统中线处Slit排斥信号的保真度至关重要，这与Sdc在中枢神经系统轴突上的定位一致。sdc突变体在中线轴突导向方面表现出一致的缺陷，以及有力且特定的遗传相互作用，支持了一种模型，即HSPG提高了Slit定位和/或信号传导的效率。为了验证这一假设，我们表明在sdc突变体中Slit分布发生了改变，并且Slit及其受体与Sdc结合。然而，当我们将跨膜Sdc的功能与定位于中枢神经系统轴突的另一类HSPG（类Dally）进行比较时，我们发现了功能冗余，这表明这些蛋白聚糖作为常见HS结构的空间特异性载体，使生长锥能够在Slit从中枢神经系统中线源处扩散时与其相互作用并感知到它。
