Anti-Mullerian-hormone-dependent regulation of the brain serine-protease inhibitor neuroserpin.
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-beta (TGFbeta)-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 TGFbeta 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.
Lebeurrier
Nathalie
N
INSERM, INSERM U919, Serine Proteases and Pathophysiology of the neurovascular Unit (SP2U), Cyceron, F-14074 France.
Launay
Séverine
S
Macrez
Richard
R
Maubert
Eric
E
Legros
Hélène
H
Leclerc
Arnaud
A
Jamin
Soazik P
SP
Picard
Jean-Yves
JY
Marret
Stéphane
S
Laudenbach
Vincent
V
Berger
Philipp
P
Sonderegger
Peter
P
Ali
Carine
C
di Clemente
Nathalie
N
Vivien
Denis
D
D000818:Animals; D054304:Anti-Mullerian Hormone / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism; D000097522:Neuroserpin
D054304:Anti-Mullerian Hormone; D052005:Bone Morphogenetic Protein Receptors, Type I; D009479:Neuropeptides; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D015843:Serpins; D051902:Smad5 Protein; D000097522:Neuroserpin; C497798:Smad5 protein, mouse; C084621:anti-Mullerian hormone receptor; C498215:Bmpr1b protein, mouse