Abstract:
Despite increasing in mass approximately 100-fold during larval life, the Drosophila CNS maintains its characteristic form. Dynamic interactions between the overlying basement membrane and underlying surface glia are known to regulate CNS structure in Drosophila, but the genes and pathways that establish and maintain CNS morphology during development remain poorly characterized. To identify genes that regulate CNS shape in Drosophila, we conducted an EMS-based, forward genetic screen of the second chromosome, uncovered 50 mutations that disrupt CNS structure, and mapped these alleles to 17 genes. Analysis of whole genome sequencing data wedded to genetic studies uncovered the affected gene for all but one mutation. Identified genes include well characterized regulators of tissue shape, like LanB1, viking, and Collagen type IV alpha1, and previously characterized genes, such as Toll-2 and Rme-8, with no known role in regulating CNS structure. We also uncovered that papilin and C1GalTA likely act in the same pathway to regulate CNS structure and found that the fly homolog of a glucuronosyltransferase, B4GAT1/LARGE1, that regulates Dystroglycan function in mammals is required to maintain CNS shape in Drosophila. Finally, we show that the senseless-2 transcription factor is expressed and functions specifically in surface glia found on peripheral nerves but not in the CNS to govern CNS structure, identifying a gene that functionally subdivides a glial subtype along the peripheral-central axis. Future work on these genes should clarify the genetic mechanisms that ensure the homeostasis of CNS form during development.
摘要:
尽管在幼虫生命期间质量增加了大约100倍,果蝇CNS保持其特征形式。已知上面的基底膜和下面的表面胶质细胞之间的动态相互作用调节果蝇的CNS结构,但是在发育过程中建立和维持CNS形态的基因和途径仍然缺乏表征。为了鉴定调节果蝇中枢神经系统形状的基因,我们进行了一个基于EMS的,第二个染色体的正向遗传筛选,发现了50个破坏CNS结构的突变,并将这些等位基因定位到17个基因上。结合遗传研究的全基因组测序数据分析发现了除一个突变外的所有突变的受影响基因。鉴定的基因包括组织形状的特征良好的调节因子,比如LanB1维京,和IV型胶原α1,以及先前表征的基因,如Toll-2和Rme-8,在调节CNS结构中没有已知的作用。我们还发现papilin和C1GalTA可能在相同的途径中调节CNS结构,并发现葡萄糖醛酸基转移酶的果蝇同源物,B4GAT1/LARGE1,调节哺乳动物体内的营养不良聚糖功能,是维持果蝇中枢神经系统形态所必需的。最后,我们表明,无意义的-2转录因子是表达和功能特异性在表面神经胶质发现的周围神经,而不是在CNS控制CNS结构,鉴定沿着外周-中心轴在功能上细分神经胶质亚型的基因。关于这些基因的未来工作应该阐明确保发育过程中CNS形式稳态的遗传机制。