ErbB受体的广谱性配体HB-EGF特异性调控中枢局域性髓鞘发育的机制研究

In our past work, we have demonstrated that different ErbB receptors in oligodendroglial lineage coordinate to regulate myelin development and integrity. Recently, through a genetically labeling approach, we found that Heparin-binding EGF-like growth factor (HB-EGF), a ligand that binds both ErbB1 and ErbB4, expresses in neurons of specific brain regions. Especially in the cerebral cortex, HB-EGF expresses in excitatory neurons of layer VI in the primary and secondary sensory cortex, including somatosensory cortex, visual cortex, and auditory cortex. Intriguingly, HB-EGF-knockout mice exhibited impaired myelin formation within the location of HB-EGF-expressing neurons and correlated callosal pathways. The phenotype of focal hypomyelination in the central nervous system of HB-EGF-knockout mice is reminiscent of focal lesions observed in the white matter of schizophrenics or patients with other psychiatric disorders, providing a potential genetic evidence to such a clinical phenotype. Our preliminary work suggested that HB-EGF regulated myelin development via a neuron-derived manner. Understanding how HB-EGF works would add the ligand information to our knowledge about how ErbB signaling pathways regulate central myelination. As a first identified molecule that regulates myelin formation specifically on a certain neural circuit, investigation of HB-EGF would help to correct our existed dogma that central myelination is generally regulated. Furthermore, behavioral analyses of HB-EGF-knockout mice would provide valuable clues of how callosal communication between the bilateral cortical regions for somatosensation, vision, or audition contributes to the related basic brain functions.

我们已揭示少突胶质细胞系中的ErbB受体协同调控中枢髓鞘的发育和完整性，近来又以遗传标记手段发现可同时激活ErbB1/4的配体HB-EGF表达于特定脑区的神经元，尤其在大脑皮层中特异表达于各种初级和次级感觉皮层的第VI层兴奋性神经元中。HB-EGF敲除鼠出现特异性的大脑后部的皮层深层和对应的胼胝体区域髓鞘发育不良的现象。这种中枢局域性髓鞘发育不良的表型，为精神分裂症等精神疾病中的局域性白质缺陷的临床表型提供了潜在的遗传机制。前期结果提示HB-EGF以神经元源性机制调控髓鞘发育。对HB-EGF的分子机制的解析将进一步完善ErbB信号通路调控中枢髓鞘发育的配体机制。作为首次被发现的调控特定神经回路髓鞘发育的关键分子，对HB-EGF作用机制的研究将修正对泛化的中枢髓鞘调控机制的认识；而对HB-EGF敲除动物的行为学分析将对研究感觉皮层间的胼胝体交通对各种感觉相关的大脑基础功能的贡献具有重要意义。

本项目在研究ErbB信号通路调控中枢髓鞘发育的长期工作基础上，集中研究表皮生长因子家族成员HB-EGF脑区特异性调控髓鞘发育的现象和机制。利用遗传标记、神经细胞蛋白标记物的检测、轴突投射逆向追踪、在体神经元HB-EGF过表达等多种手段，我们确定在大脑皮层中HB-EGF特异性表达在感觉皮层（躯体感觉皮层、视觉皮层、听觉皮层）的第VI层的胼胝体投射神经元，以旁分泌的方式从其轴突释放，调控感觉皮层相互交通的胼胝体投射路径上的少突胶质细胞增殖和分化，促进该特定神经回路上的髓鞘发育。进一步研究少突胶质细胞中的ErbB信号通路，我们发现与刺激的ErbB配体对受体的结合特异性无关，细胞中所有ErbB受体协同调控少突胶质细胞的分化成熟，以及成熟少突胶质细胞的有氧糖酵解产生乳酸的能力。通过对特异性靶向少突胶质细胞不同分化阶段的动物模型的研究，我们发现ErbB信号通路紊乱既可通过造成髓鞘发育不良、也可通过减少对电活跃的神经回路中神经轴突的乳酸供应来削弱动物的工作记忆。该研究明确了ErbB信号通路对中枢髓鞘发育和功能的重要调控作用，阐述了中枢髓鞘调控大脑高级功能的多种方式；并首次提供了HB-EGF为中枢神经系统局域性髓鞘发育的关键调控分子的明确证据，提示脑区特异性ErbB信号通路调控分子机制的紊乱可能参与精神疾病的局域性白质损伤现象。