The Glucuronyltransferase GlcAT-P Is Required for Stretch Growth of Peripheral Nerves in Drosophila

During development, the growth of the animal body is accompanied by a concomitant elongation of the peripheral nerves, which requires the elongation of integrated nerve fibers and the axons projecting therein. Although this process is of fundamental importance to almost all organisms of the animal kingdom, very little is known about the mechanisms regulating this process. Here, we describe the identification and characterization of novel mutant alleles of GlcAT-P, the Drosophila ortholog of the mammalian glucuronyltransferase b3gat1. GlcAT-P mutants reveal shorter larval peripheral nerves and an elongated ventral nerve cord (VNC). We show that GlcAT-P is expressed in a subset of neurons in the central brain hemispheres, in some motoneurons of the ventral nerve cord as well as in central and peripheral nerve glia. We demonstrate that in GlcAT-P mutants the VNC is under tension of shorter peripheral nerves suggesting that the VNC elongates as a consequence of tension imparted by retarded peripheral nerve growth during larval development. We also provide evidence that for growth of peripheral nerve fibers GlcAT-P is critically required in hemocytes; however, glial cells are also important in this process. The glial specific repo gene acts as a modifier of GlcAT-P and loss or reduction of repo function in a GlcAT-P mutant background enhances VNC elongation. We propose a model in which hemocytes are required for aspects of glial cell biology which in turn affects the elongation of peripheral nerves during larval development. Our data also identifies GlcAT-P as a first candidate gene involved in growth of integrated peripheral nerves and therefore establishes Drosophila as an amenable in-vivo model system to study this process at the cellular and molecular level in more detail.

在动物发育过程中，体躯生长伴随外周神经的同步伸长，这一过程要求整合神经纤维及其内部投射的轴突一同伸长。尽管该过程对动物界几乎所有类群都具有核心重要性，但目前对调控该过程的分子机制仍所知甚少。
本研究报道了哺乳动物葡萄糖醛酸转移酶b3gat1（glucuronyltransferase b3gat1）的果蝇（Drosophila）同源基因GlcAT-P的新型突变等位基因的鉴定与表征。GlcAT-P突变体幼虫表现出外周神经缩短、腹神经索（ventral nerve cord, VNC）伸长的表型。
我们发现，GlcAT-P在大脑半球的部分神经元、腹神经索中的部分运动神经元，以及中枢和外周神经胶质细胞中均有表达。
我们证实，在GlcAT-P突变体中，腹神经索处于较短外周神经的牵拉张力之下，提示腹神经索的伸长是幼虫发育阶段外周神经生长迟缓所产生的张力介导的结果。
我们还提供证据表明，GlcAT-P在血细胞（hemocytes）中对外周神经纤维的生长发挥关键作用；同时胶质细胞在该过程中也具有重要功能。
胶质细胞特异性基因repo作为GlcAT-P的修饰基因，在GlcAT-P突变的遗传背景下，repo功能的缺失或下调会加剧腹神经索的伸长表型。
我们提出了一个模型：血细胞参与调控胶质细胞的生物学过程，而后者进而影响幼虫发育期间外周神经的伸长。
本研究数据还首次将GlcAT-P鉴定为参与整合性外周神经生长的候选基因，因此确立了果蝇作为可用于在细胞与分子水平上更细致研究该过程的合适体内（in-vivo）模型系统。