Copf Tijana, Kamara Mildred, Venkatesh Tadmiri
a Department of Biology, City College of New York , City University of New York (CUNY) , New York , NY , USA.
b Institute of Molecular Biology and Biotechnology , Heraklion , Greece.
J Neurogenet. 2019 Sep;33(3):157-163. doi: 10.1080/01677063.2019.1586896. Epub 2019 Apr 8.
Axonal extension and synaptic targeting are usually completed during early development, but the axonal length and synaptic integrity need to be actively maintained during later developmental stages and the adult life. Failure in the axonal length maintenance and the subsequent axonal degeneration have been associated with neurological disorders, but currently little is known about the genetic factors controlling this process. Here, we show that regulated intracellular levels of cAMP-dependent protein kinase A (PKA) are critical for the axon maintenance during the transition from the early to the later larval stages in the Drosophila class IV dendritic arborization (da) sensory neurons. Our data indicate that when the intracellular levels of PKA are increased via genetic manipulations, these peripheral neurons initially form synapses with wild-type appearance, at their predicted ventral nerve cord (VNC) target sites (in the first and second instar larval stages), but that their synapses disintegrate, and the axons retract and become fragmented in the subsequent larval stages (third larval stage). The affected axonal endings at the disintegrated synaptic sites still express the characteristic presynaptic and cytoskeletal markers such as Bruchpilot and Fascin, indicating that the synapse had been initially properly formed, but that it later lost its integrity. Finally, the phenotype is significantly more prominent in the axons of the neurons whose cell bodies are located in the posterior body segments. We propose that the reason for this is the fact that during the larval development the posterior neurons face a much greater challenge while trying to keep up with the fast-paced growth of the larval body, and that PKA is critical for this process. Our data reveal PKA as a novel factor in the axonal length and synapse integrity maintenance in sensory neurons. These results could be of help in understanding neurological disorders characterized by destabilized synapses.
轴突延伸和突触靶向通常在早期发育过程中完成，但在后期发育阶段和成年期，轴突长度和突触完整性需要积极维持。轴突长度维持失败及随后的轴突退化与神经疾病有关，但目前对控制这一过程的遗传因素知之甚少。在这里，我们表明，在果蝇IV类树突状分支（da）感觉神经元从幼虫早期向后期转变过程中，调节细胞内依赖环磷酸腺苷的蛋白激酶A（PKA）水平对于轴突维持至关重要。我们的数据表明，当通过基因操作提高PKA的细胞内水平时，这些外周神经元最初在其预测的腹侧神经索（VNC）靶位点（在第一和第二龄幼虫阶段）形成外观正常的突触，但在随后的幼虫阶段（第三龄幼虫阶段），它们的突触解体，轴突缩回并碎片化。在解体的突触位点处受影响的轴突末梢仍表达特征性的突触前和细胞骨架标记物，如bruchpilot和Fascin，这表明突触最初形成正常，但后来失去了完整性。最后，在细胞体位于身体后部节段的神经元轴突中，这种表型更为明显。我们认为原因在于，在幼虫发育过程中，后部神经元在试图跟上幼虫身体快速生长的过程中面临更大的挑战，而PKA对这一过程至关重要。我们的数据揭示PKA是感觉神经元轴突长度和突触完整性维持中的一个新因素。这些结果可能有助于理解以突触不稳定为特征的神经疾病。
