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First published online 16 September 2008
doi: 10.1242/jcs.031872

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Anti-Mullerian-hormone-dependent regulation of the brain serine-protease inhibitor neuroserpin

Nathalie Lebeurrier^1,2,3,*, Séverine Launay^1,2,3,*, Richard Macrez^1,2,3, Eric Maubert^1,2,3, Hélène Legros⁴, Arnaud Leclerc^5,6, Soazik P. Jamin^5,6, Jean-Yves Picard^5,6, Stéphane Marret⁴, Vincent Laudenbach⁴, Philipp Berger^7,, Peter Sonderegger⁷, Carine Ali^1,2,3, Nathalie di Clemente^5,6 and Denis Vivien^1,2,3,

¹ INSERM, INSERM U919, Serine Proteases and Pathophysiology of the neurovascular Unit (SP2U), Cyceron, F-14074 France
² CNRS, UMR CNRS 6232 Ci-NAPs `Center for imaging Neurosciences and Applications to PathologieS', Cyceron, F-14074 France
³ University of Caen Basse-Normandie, Caen Cedex, F-14074 France
⁴ INSERM-Avenir, Institute for Biomedical Research, IFRMP23, University of Rouen & Department of Neonatal Pediatrics and Intensive Care, Rouen University Hospital, Rouen, F-76183, France
⁵ INSERM, U782, Clamart, F-92140
⁶ University of Paris-Sud, UMR-S0782, Clamart, F-92140
⁷ Department of Biochemistry, University of Zurich, Zurich, CH-8057, Switzerland

Author for correspondence (e-mail: vivien{at}cyceron.fr)

Accepted 30 June 2008

The balance between tissue-type plasminogen activator (tPA) and one of its inhibitors, neuroserpin, has crucial roles in the central nervous system, including the control of neuronal migration, neuronal plasticity and neuronal death. In the present study, we demonstrate that the activation of the transforming growth factor-β (TGFβ)-related BMPR-IB (also known as BMPR1B and Alk6)- and Smad5-dependent signalling pathways controls neuroserpin transcription. Accordingly, we demonstrate for the first time that anti-Mullerian hormone (AMH), a member of the TGFβ family, promotes the expression of neuroserpin in cultured neurons but not in astrocytes. The relevance of these findings is confirmed by the presence of both AMH and AMH type-II receptor (AMHR-II) in brain tissues, and is supported by the observation of reduced levels of neuroserpin in the brain of AMHR-II-deficient mice. Interestingly, as previously demonstrated for neuroserpin, AMH protects neurons against N-methyl-D-aspartate (NMDA)-mediated excitotoxicity both in vitro and in vivo. This study demonstrates the existence of an AMH-dependent signalling pathway in the brain leading to an overexpression of the serine-protease inhibitor, neuroserpin, and neuronal survival.

Key words: Neuroserpin, Transcription, Anti-Mullerian hormone (AMH), Neuron, Brain, Serpin