Wegrzyn David, Zokol Josephine, Faissner Andreas
Department of Cell Morphology and Molecular Neurobiology, Ruhr-University Bochum, Bochum, Germany.
Front Cell Neurosci. 2022 Feb 14;15:817277. doi: 10.3389/fncel.2021.817277. eCollection 2021.
Vav proteins belong to the class of guanine nucleotide exchange factors (GEFs) that catalyze the exchange of guanosine diphosphate (GDP) by guanosine triphosphate (GTP) on their target proteins. Here, especially the members of the small GTPase family, Ras homolog family member A (RhoA), Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 homolog (Cdc42) can be brought into an activated state by the catalytic activity of Vav-GEFs. In the central nervous system (CNS) of rodents Vav3 shows the strongest expression pattern in comparison to Vav2 and Vav1, which is restricted to the hematopoietic system. Several studies revealed an important role of Vav3 for the elongation and branching of neurites. However, little is known about the function of Vav3 for other cell types of the CNS, like astrocytes. Therefore, the following study analyzed the effects of a knockout on several astrocytic parameters as well as the influence of Vav3-deficient astrocytes on the dendritic development of cultured neurons. For this purpose, an indirect co-culture system of native hippocampal neurons and Vav3-deficient cortical astrocytes was used. Interestingly, neurons cultured in an indirect contact with Vav3-deficient astrocytes showed a significant increase in the dendritic complexity and length after 12 and 17 days (DIV). Furthermore, Vav3-deficient astrocytes showed an enhanced regeneration in the scratch wound heal assay as well as an altered profile of released cytokines with a complete lack of CXCL11, reduced levels of IL-6 and an increased release of CCL5. Based on these observations, we suppose that Vav3 plays an important role for the development of dendrites by regulating the expression and the release of neurotrophic factors and cytokines in astrocytes.
Vav蛋白属于鸟嘌呤核苷酸交换因子（GEF）家族，可催化靶蛋白上的鸟苷二磷酸（GDP）与鸟苷三磷酸（GTP）发生交换。在此过程中，小GTPase家族成员，特别是Ras同源家族成员A（RhoA）、Ras相关的C3肉毒杆菌毒素底物1（Rac1）和细胞分裂控制蛋白42同源物（Cdc42）可通过Vav-GEFs的催化活性进入激活状态。在啮齿动物的中枢神经系统（CNS）中，与Vav2和Vav1相比，Vav3表现出最强的表达模式，而Vav2和Vav1仅限于造血系统。多项研究表明Vav3在神经突的伸长和分支中发挥重要作用。然而，关于Vav3对中枢神经系统其他细胞类型（如星形胶质细胞）的功能了解甚少。因此，以下研究分析了敲除Vav3对多个星形胶质细胞参数的影响以及Vav3缺陷型星形胶质细胞对培养神经元树突发育的影响。为此，使用了原代海马神经元和Vav3缺陷型皮质星形胶质细胞的间接共培养系统。有趣的是，与Vav3缺陷型星形胶质细胞间接接触培养的神经元在培养12天和17天（DIV）后，树突复杂性和长度显著增加。此外，Vav3缺陷型星形胶质细胞在划痕伤口愈合试验中显示出增强的再生能力，并且释放的细胞因子谱发生改变，完全缺乏CXCL11，IL-6水平降低，CCL5释放增加。基于这些观察结果，我们推测Vav3通过调节星形胶质细胞中神经营养因子和细胞因子的表达和释放，在树突发育中发挥重要作用。
