轴突成束被认为是神经回路形成和功能的关键步骤。最近的研究揭示了轴突成束形成的各种分子机制;然而,轴突成束的影响,和它的必然结果,蠕动,神经电路布线仍不清楚。感觉运动皮层中的皮质脊髓(CS)神经元将轴突投射到脊髓以控制熟练的运动。在啮齿动物中,轴突在大脑中保持紧密的束状,并穿过脊髓的背侧。在这里,我们显示了plexinA1(PlexA1)和plexinA3(PlexA3)受体由CS神经元表达,而它们的配体,semaphorin-5A(Sema5A)和semaphorin-5B(Sema5B)在CS轴突的截流部位的髓质中表达,以抑制这些轴突的过早蠕动。在没有Sema5A/5B-PlexA1/A3信令的情况下,一些CS轴突在脑干的髓质中过早地萎缩,以及那些在脊髓灰质而不是脊髓背侧筋膜中异常横行的CS轴突。在没有Sema5A/Sema5B-PlexA1/A3信号时,CS轴突,通常会支配腰脊髓,在脊髓灰质中被解开,过早地支配宫颈灰质,而腰椎灰质的神经支配减少。在Sema5A/5B和PlexA1/A3突变小鼠(两种性别)中,异常刺激后肢运动皮层会引起前肢肌肉的强烈激活。最后,Sema5A/5B和PlexA1/A3突变小鼠在熟练运动中表现出缺陷。这些结果表明,适当的神经电路布线需要适当的CS轴突束感,并最终影响进行熟练运动的能力。意义陈述:轴突成束被认为对神经回路的形成和功能至关重要。然而,轴突成束缺陷是否以及如何影响神经回路的形成和功能尚不清楚。在这里,我们检查跨膜蛋白信号量-5A(Sema5A)和信号量-5B(Sema5B),和它们的受体,plexinA1(PlexA1)和plexinA3(PlexA3)在皮质脊髓回路的发育中起作用。我们发现Sema5A/Sema5B和PlexA1/A3是皮质脊髓神经元适当轴突成束所必需的。此外,Sema5A/5B和PlexA1/A3突变小鼠在熟练的运动行为中显示出明显的缺陷。因此,这些结果强烈表明,小鼠皮质脊髓回路的适当形成和功能需要适当的皮质脊髓轴突成束。
Axon fasciculation is thought to be a critical step in neural circuit formation and function. Recent studies have revealed various molecular mechanisms that underlie axon fasciculation; however, the impacts of axon fasciculation, and its corollary, defasciculation, on neural circuit wiring remain unclear. Corticospinal (CS) neurons in the sensorimotor cortex project axons to the spinal cord to control skilled movements. In rodents, the axons remain tightly fasciculated in the brain and traverse the dorsal funiculus of the spinal cord. Here we show that plexinA1 (PlexA1) and plexinA3 (PlexA3) receptors are expressed by CS neurons, whereas their ligands,
semaphorin-5A (Sema5A) and
semaphorin-5B (Sema5B) are expressed in the medulla at the decussation site of CS axons to inhibit premature defasciculation of these axons. In the absence of Sema5A/5B-PlexA1/A3 signaling, some CS axons are prematurely defasciculated in the medulla of the brainstem, and those defasciculated CS axons aberrantly transverse in the spinal gray matter instead of the spinal dorsal funiculus. In the absence of Sema5A/Sema5B-PlexA1/A3 signaling, CS axons, which would normally innervate the lumbar spinal cord, are unbundled in the spinal gray matter, and prematurely innervate the cervical gray matter with reduced innervation of the lumbar gray matter. In both Sema5A/5B and PlexA1/A3 mutant mice (both sexes), stimulation of the hindlimb motor cortex aberrantly evokes robust forelimb muscle activation. Finally, Sema5A/5B and PlexA1/A3 mutant mice show deficits in skilled movements. These results suggest that proper fasciculation of CS axons is required for appropriate neural circuit wiring and ultimately affect the ability to perform skilled movements.SIGNIFICANCE STATEMENT Axon fasciculation is believed to be essential for neural circuit formation and function. However, whether and how defects in axon fasciculation affect the formation and function of neural circuits remain unclear. Here we examine whether the transmembrane proteins
semaphorin-5A (Sema5A) and
semaphorin-5B (Sema5B), and their receptors, plexinA1 (PlexA1) and plexinA3 (PlexA3) play roles in the development of corticospinal circuits. We find that Sema5A/Sema5B and PlexA1/A3 are required for proper axon fasciculation of corticospinal neurons. Furthermore, Sema5A/5B and PlexA1/A3 mutant mice show marked deficits in skilled motor behaviors. Therefore, these results strongly suggest that proper corticospinal axon fasciculation is required for the appropriate formation and functioning of corticospinal circuits in mice.