Max-Delbrück-Center, Robert-Rössle-Str. 10, 13092 Berlin, Germany.
Interfaculty Institute of Biochemistry, University of Tübingen, Hoppe-Seyler-Str. 4, 72076 Tübingen, Germany.
Int J Mol Sci. 2018 Apr 24;19(5):1266. doi: 10.3390/ijms19051266.
Axonal branching is a key process in the establishment of circuit connectivity within the nervous system. Molecular-genetic studies have shown that a specific form of axonal branching—the bifurcation of sensory neurons at the transition zone between the peripheral and the central nervous system—is regulated by a cyclic guanosine monophosphate (cGMP)-dependent signaling cascade which is composed of C-type natriuretic peptide (CNP), the receptor guanylyl cyclase Npr2, and cGMP-dependent protein kinase Iα (cGKIα). In the absence of any one of these components, neurons in dorsal root ganglia (DRG) and cranial sensory ganglia no longer bifurcate, and instead turn in either an ascending or a descending direction. In contrast, collateral axonal branch formation which represents a second type of axonal branch formation is not affected by inactivation of CNP, Npr2, or cGKI. Whereas axon bifurcation was lost in mouse mutants deficient for components of CNP-induced cGMP formation; the absence of the cGMP-degrading enzyme phosphodiesterase 2A had no effect on axon bifurcation. Adult mice that lack sensory axon bifurcation due to the conditional inactivation of Npr2-mediated cGMP signaling in DRG neurons demonstrated an altered shape of sensory axon terminal fields in the spinal cord, indicating that elaborate compensatory mechanisms reorganize neuronal circuits in the absence of bifurcation. On a functional level, these mice showed impaired heat sensation and nociception induced by chemical irritants, whereas responses to cold sensation, mechanical stimulation, and motor coordination are normal. These data point to a critical role of axon bifurcation for the processing of acute pain perception.
轴突分支是神经系统中建立回路连接的关键过程。分子遗传学研究表明，一种特定形式的轴突分支——感觉神经元在外周和中枢神经系统交界处的分支——是由环鸟苷酸（cGMP）依赖性信号级联调节的，该级联由 C 型利钠肽（CNP）、受体鸟苷酸环化酶 Npr2 和 cGMP 依赖性蛋白激酶 Iα（cGKIα）组成。在这些成分中的任何一种缺失的情况下，背根神经节（DRG）和颅神经节中的神经元不再分支，而是向上或向下转向。相比之下，不影响 CNP、Npr2 或 cGKI 失活的侧支轴突分支形成代表了第二种轴突分支形成类型。虽然在 CNP 诱导的 cGMP 形成成分缺失的小鼠突变体中，轴突分支丧失；但 cGMP 降解酶磷酸二酯酶 2A 的缺失对轴突分支没有影响。由于 DRG 神经元中 Npr2 介导的 cGMP 信号转导的条件性失活，成年小鼠丧失了感觉轴突分支，脊髓中的感觉轴突末端场的形状发生改变，表明在没有分支的情况下，复杂的代偿机制会重新组织神经元回路。在功能水平上，这些小鼠对化学刺激引起的热感觉和痛觉感知受损，而对冷感觉、机械刺激和运动协调的反应正常。这些数据表明轴突分支对急性疼痛感知的处理起着关键作用。
