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Séminaire - Isabelle BrunetNetrin-1 guides sympathetic arterial innervation

Abstract :

 Autonomic sympathetic nerves innervate peripheral resistance arteries,
thereby regulating vascular tone and controlling blood supply to organs. Despite the fundamental importance of blood flow control, how sympathetic arterial innervation develops remains largely unknown. We identified the axon guidance cue netrin-1 as an essential factor required for development of arterial innervation in mice.
Netrin-1 is produced by arterial smooth muscle cells (SMCs) at the onset of innervation, and arterial innervation require the interaction of Netrin-1 with its receptor, deleted in colorectal cancer (DCC), on sympathetic growth cones. Function-blocking approaches, including cell type-specific deletion of the genes encoding Ntn1 in SMCs and Dcc in sympathetic neurons, led to severe and selective reduction of sympathetic innervation and to defective vasoconstriction in resistance arteries.

These findings indicate that netrin-1 and DCC are critical for the control of arterial innervation and blood flow regulation in peripheral organs.

Selected publications

Eichmann A & Brunet I. Arterial innervation in health and disease. Science Translational Medecine (2014). Sept 3, 6(252)
Brunet I#, Emma Gordon, Jinah Han, Brunella Cristofaro, Dong Broqueres-You, Chun Liu, Karine Bouvrée, Jiasheng Zhang, Raquel del Toro, Thomas Mathivet, Bruno Larrivée, Julia Jagu, Laurence Pibouin-Fragner, Luc Pardanaud, Maria J. C. Machado, Timothy E. Kennedy,Zhen Zhuang, Michael Simons, Bernard I. Levy, Marc Tessier-Lavigne Almut Grenz, Holger Eltzschig and Anne Eichmann#. Netrin-1 guides sympathetic arterial innervation. Journal of Clinical Investigation, (2014) 124(7):3230–3240. # corresponding author

Bouvrée K*, Brunet I*, Del Toro R, Prahst C, Gordon E, Cristofaro B, Xu Y, Soueid J, Fortuna V, Miura N, Aigrot MS, Maden CH, Ruhrberg C, Thomas JL, Eichmann A.Semaphorin3A, Neuropilin-1 and PlexinA1 are required for lymphatic valve formation. Circ Res. (2012) Aug 3;111(4):437-45. * equal contribution

Wizenmann A*, Brunet I*, Lam JS, Sonnier L, Beurdeley M, Zarbalis K,Weisenhorn-Vogt D, Weinl C, Dwivedy A, Joliot A, Wurst W, Holt C, Prochiantz A. Extracellular Engrailed participates in the topographic guidance of retinal axons in vivo. Neuron (2009).64(3):355-66. * equal contribution

Brunet I, Sonnier L, Di Nardo A, Beurdeley M, and Prochiantz A. The topological role of homeoproteins in the developing central nervous system.TINS Review (2007) 30 (6/ 260-267) sur invitation de J. Flanagan

Brunet I, Weinl C, Piper M, Trembleau A, Volovitch M, Harris W, Prochiantz A, and Holt CE The transcription factor Engrailed-2 guides retinal axons. Nature (2005) 438 (94-98)

Scientific focus :

Principal Investigator: Isabelle BRUNET, CR1 Inserm

Neuronal and vascular development require a refined spatio-temporal orchestration to guide axons and vascular plexus through the organism, align vessels with nerves, and allow appropriate functional connections to establish between the two systems. My reasearch project is at the interface between two disciplines, neurosciences and vascular biology, to study neurovascular interactions, focusing on arterial innervation.
Very little is currently known about neurovascular development and biology, as this area of research is relatively young. In order to elucidate the functional aspects of neurovascular interactions, such as the mechanisms underlying the coupling between neural activity and vascular dynamics or arterial innervation and vascularization of nerves, we must first understand and characterize the anatomical aspects of the neurovascular interactions.
To study these questions in vivo, we use genetically engineered mouse models with tissue-specific mutations and tracers combined with imaging and physiological approaches such as laser doppler and telemetry. To complement this work, we also perform studies in chick and a variety of in vitro assays to further reveal the mechanisms of action.

Those approaches will allow us to understand the neurovascular interactions from a molecular level to the organism level. My current project aim to decipher the molecular control of arterial innervation and its physiological/functional consequences