Venous endothelin modulates responsiveness of cardiac sympathetic axons to arterial semaphorin
Denise M Poltavski,
Pauline Colombier,
Jianxin Hu,
Alicia Duron,
Brian L Black,
Takako Makita
Affiliations
Denise M Poltavski
The Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, United States
Pauline Colombier
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Jianxin Hu
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Alicia Duron
The Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, United States; Darby Children’s Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, United States
The Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, United States; Darby Children’s Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, United States
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.
