Division of Biological and Biomedical Systems, University of Missouri-Kansas City, 5009 Rockhill Road, Kansas City, MO 64110, USA.
Department of Genetics, Washington University School of Medicine, 4523 Clayton Avenue, St. Louis, MO 63110, USA.
G3 (Bethesda). 2024 Sep 4;14(9). doi: 10.1093/g3journal/jkae152.
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 1 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.
尽管在幼虫生命过程中质量增加了约 100 倍，但果蝇中枢神经系统仍然保持其特有的形态。已知覆盖基底膜和下表面神经胶质之间的动态相互作用可以调节果蝇中枢神经系统的结构，但在发育过程中建立和维持中枢神经系统形态的基因和途径仍未得到充分描述。为了鉴定调控果蝇中枢神经系统形状的基因，我们在第二染色体上进行了基于 EMS 的正向遗传筛选，发现了 50 个破坏中枢神经系统结构的突变，并将这些等位基因映射到 17 个基因上。全基因组测序数据的分析与遗传研究相结合，揭示了除 1 个突变外的所有受影响基因。鉴定的基因包括组织形状的特征调节剂，如 LanB1、viking 和胶原 type IV alpha1，以及以前表征的基因，如 Toll-2 和 Rme-8，它们在调节中枢神经系统结构方面没有已知的作用。我们还发现 papilin 和 C1GalTA 可能在相同的途径中起作用来调节中枢神经系统的结构，并且发现了在哺乳动物中调节 Dystroglycan 功能的糖基转移酶 B4GAT1/LARGE1 的果蝇同源物是维持果蝇中枢神经系统形状所必需的。最后，我们表明 senseless-2 转录因子在位于外围神经上的表面神经胶质中表达并特异性起作用，但不在中枢神经系统中起作用，以控制中枢神经系统的结构，鉴定了一个沿外围-中枢轴将神经胶质亚型功能细分的基因。对这些基因的进一步研究应该阐明确保中枢神经系统在发育过程中保持形态稳定性的遗传机制。
