Venous endothelin modulates responsiveness of cardiac sympathetic axons to arterial semaphorin.
Developing neurons of the peripheral nervous system reach their targets via cues that support directional growth, a process known as axon guidance. In investigating how sympathetic axons reach the heart in mice, we discovered that a combination of guidance cues are employed in sequence to refine axon outgrowth, a process we term second-order guidance. Specifically, endothelin-1 induces sympathetic neurons expressing the receptor Ednra to project to the vena cavae leading to the heart. Endothelin signaling in turn induces expression of the repulsive receptor Plexin-A4, via induction of the transcription factor MEF2C. In the absence of endothelin or plexin signaling, sympathetic neurons misproject to incorrect competing vascular trajectories (the dorsal aorta and intercostal arteries). The same anatomical and physiological consequences occur in Ednra+/-; Plxna4+/- double heterozygotes, genetically confirming functional interaction. Second-order axon guidance therefore multiplexes a smaller number of guidance cues in sequential fashion, allowing precise refinement of axon trajectories.
['Poltavski|Denise M|DM|', 'Colombier|Pauline|P|', 'Hu|Jianxin|J|', 'Duron|Alicia|A|', 'Black|Brian L|BL|0000-0002-6664-8913', 'Makita|Takako|T|0000-0002-5598-5690']
D000818:Animals D001158:Arteries D000071437:Axon Guidance D001369:Axons D016232:Endothelins D018507:Gene Expression Regulation, Developmental D006321:Heart D006579:Heterozygote D064326:MEF2 Transcription Factors D051379:Mice D018345:Mice, Knockout D009419:Nerve Tissue Proteins D055495:Neurogenesis D009474:Neurons D044022:Receptor, Endothelin A D011956:Receptors, Cell Surface D039961:Semaphorins D015398:Signal Transduction D013564:Sympathetic Nervous System D014684:Venae Cavae
axon guidance developmental biology heart innervation mouse neuroscience sympathetic nerves