Motor neurons use push-pull signals to direct vascular remodeling critical for their connectivity

• Published in: Neuron (Cambridge, Mass.) Vol. 110; no. 24; pp. 4090 - 4107.e11
• Main Authors: Martins, Luis F., Brambilla, Ilaria, Motta, Alessia, de Pretis, Stefano, Bhat, Ganesh Parameshwar, Badaloni, Aurora, Malpighi, Chiara, Amin, Neal D., Imai, Fumiyasu, Almeida, Ramiro D., Yoshida, Yutaka, Pfaff, Samuel L., Bonanomi, Dario
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.12.2022
• Subjects: Animals; axon guidance; Axons - metabolism; cell signaling; cell-cell interactions; Endothelial Cells - metabolism; forward genetics; Mice; motor neurons; Motor Neurons - metabolism; neural circuits; neurovascular patterning; semaphorin/plexin; Semaphorins - metabolism; spinal cord; Spinal Cord - metabolism; Vascular Remodeling; VEGF; motor neurons; VEGF; neural circuits; cell signaling; semaphorin/plexin; spinal cord; axon guidance; neurovascular patterning; forward genetics; cell-cell interactions
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2022.09.021

The nervous system requires metabolites and oxygen supplied by the neurovascular network, but this necessitates close apposition of neurons and endothelial cells. We find motor neurons attract vessels with long-range VEGF signaling, but endothelial cells in the axonal pathway are an obstacle for establishing connections with muscles. It is unclear how this paradoxical interference from heterotypic neurovascular contacts is averted. Through a mouse mutagenesis screen, we show that Plexin-D1 receptor is required in endothelial cells for development of neuromuscular connectivity. Motor neurons release Sema3C to elicit short-range repulsion via Plexin-D1, thus displacing endothelial cells that obstruct axon growth. When this signaling pathway is disrupted, epaxial motor neurons are blocked from reaching their muscle targets and concomitantly vascular patterning in the spinal cord is altered. Thus, an integrative system of opposing push-pull cues ensures detrimental axon-endothelial encounters are avoided while enabling vascularization within the nervous system and along peripheral nerves. [Display omitted] •Plexin-D1 is required in ECs to establish axial MN connectivity•MNs release attractive and repulsive signals that pattern blood vessels•Motor axons displace endothelial obstacles with Sema3C/Plexin-D1 signaling•Neurovascular crosstalk links axon targeting of neuronal subtypes to vascularization Axons navigate complex environments where unwanted encounters with other cells might hinder their course. Martins et al. identify a selective obstacle-removal pathway based on short-range Sema3C/Plexin-D1 repulsive signaling that motor neurons employ to evade collisions with blood vessels while enabling assembly of interdependent neurovascular networks through attraction of endothelial cells.