Abstract
BackgroundThe development of the corticospinal tract (CST) in higher vertebrates relies on a series of axon guidance decisions along its long projection pathway. Several guidance molecules are known to be involved at various decision points to regulate the projection of CST axons. However, previous analyses of the CST guidance defects in mutant mice lacking these molecules have suggested that there are other molecules involved in CST axon guidance that are yet to be identified. In this study, we investigate the role of plexin signaling in the guidance of motor CST axons in vivo.ResultsExpression pattern studies show that plexin-A3, plexin-A4, and neuropilin-1 are expressed in the developing cerebral cortex when the motor CST axons originating from layer V cortical neurons are guided down to the spinal cord. By analyzing mutant mice, we show that motor CST axons that turn dorsally to cross the midline at the pyramidal decussation require plexin-A3 and plexin-A4 signaling. Although other CST guidance defects are found in neuropilin-1 mutants, this dorsal turning defect is not observed in either neuropilin-1 or neuropilin-2 mutants, suggesting that the local cues that activate plexin signaling at the dorsal turning point are membrane-bound semaphorins. Further expression pattern study and mutant analysis indicate that Sema6A is one of the local cues for motor CST axon turning at the pyramidal decussation.ConclusionDorsal turning and midline crossing at the pyramidal decussation is a crucial step to properly direct CST axons into the dorsal spinal cord. We show that the signaling of plexin-A3, plexin-A4, and Sema6A is at least partially required for dorsal turning of the CST axons, while neuropilin-1 is required for proper fasciculation of the tract at midline crossing. Together with previous reports, these results demonstrate that several guidance cues are specifically utilized to regulate the dorsal turning and midline crossing of developing CST axons.
Highlights
The development of the corticospinal tract (CST) in higher vertebrates relies on a series of axon guidance decisions along its long projection pathway
The expression of plexin-A3, plexin-A4, and neuropilin-1 in cortical neurons coincides with the guidance of motor CST axons To address whether semaphorin signaling through plexins regulates the guidance of CST axons, we focused on PLXA3 and PLXA4, as well as neuropilins, NPN-1 and NPN-2, and analyzed their expression patterns in the developing neocortex
By P3, once most CST axons have reached their targets in the spinal cord, NPN-1 expression in the cortex was reduced while PLXA3 and PLXA4 expression levels were maintained
Summary
The development of the corticospinal tract (CST) in higher vertebrates relies on a series of axon guidance decisions along its long projection pathway. Several guidance molecules are known to be involved at various decision points to regulate the projection of CST axons. The corticospinal tract (CST) represents the longest projection pathway in the CNS of higher vertebrates [4,5,6,7,8]. The CST axons originate from layer V cortical pyramidal neurons [7]. They exit the neocortex through the internal capsule and cerebral peduncle. The targeting of primary CST axons to the spinal cord is followed by axon collateral branching to several target areas and by pruning of specific collateral branches [7,9]
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