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Etude de la voie de signalisation Sonic Hedgehog et du contrôle de la prolifération cellulaire dans le cerveau mature de rongeurs

Abstract : The morphogen Sonic Hedgehog (Shh) displays a complex signaling pathway mainly studied during the embryonic development, where Shh is of primary importance for the development of central nervous system. Shh transmits its action via the Patched/Smoothened complex-receptor (Ptc/Smo) and Gli1 transcription factor, and interacts with the Hip (Hedgehog interacting protein) glycoprotein proposed to act as antagonist of the Hedgehog proteins. Biochemical analyses have shown that in addition to the membrane form, a soluble form of Hip exists, in particular in the adult brain, and inhibits Shh pathway in vitro. In addition, Hip expression pattern in the embryonic (E13.5) and adult mouse brain clearly support a role for Hip in the negative regulation of the Shh pathway. Finally the expression of Hip in cells producing the nitric oxide (NO) synthase in the mature brain suggests interactions between Hip and NO neurotransmitter gas signaling pathways. To evaluate the effects of Shh on neural precursor cells of the adult mouse forebrain, we performed stereotaxically guided delivery of recombinant ShhN into the lateral ventricles (LV) of adult mouse brain. In addition to a strong activation of the Shh pathway, reflected by the increase in the transcription of Ptc and Gli1 in several cerebral areas, such as the subventricular zone (SVZ), striatum, lateral septum, corpus callosum and cerebral cortex, the number of cells having incorporated the Bromodésoxyuridine (BrdU) proliferation marker, was increased by a factor 3-4 in the corpus callosum and the cerebral cortex of the ShhN injected mice compared to control mice. However, such an increase was not observed in the SVZ, a major neurogenic area in the mature brain. In addition, two days after the injection of ShhN, a more significantly higher number of proliferating cells expressing the proteoglycan NG2, marker of oligodendroglial precursors, was observed in the cerebral cortex of the mice having received the ShhN protein. In order to analyze the long-term effect of Shh overexpression, an adenoviral vector Ad5-hShh-ires-eGFP intended to express human form of Shh protein was developed then characterized in vitro. This vector was then delivered in the LV adult mice and four days after, the Shh protein was detected in brian ependymal and subependymal areas. Twenty-six days after the injection of the Ad5-hShh-ires-eGFP vector, the Shh pathway was still active as revealed by the presence of many cells expressing Gli1 in several cerebral surfaces. An increase of 50% of the number of BrdU+ cells expressing the oligodendroglial marker dm20+ has been detected in the cerebral cortex and the corpus callosum of Ad5-hShhires-eGFP injected mice compared to the Ad5-eGFP control mice. Altogether, these results reveal the capability of Shh to stimulate the proliferation of oligodendroglial precursors in several areas of adult rodent brains. Keeping with that, the modulation of the Shh pathway thus appears potentially interesting for the treatment of the diseases affecting the oligodendroglial lineage.
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Contributor : Karine Loulier <>
Submitted on : Tuesday, November 3, 2009 - 10:45:53 AM
Last modification on : Friday, October 23, 2020 - 4:41:47 PM


  • HAL Id : tel-00429497, version 1



Karine Loulier. Etude de la voie de signalisation Sonic Hedgehog et du contrôle de la prolifération cellulaire dans le cerveau mature de rongeurs. Neurosciences [q-bio.NC]. Université Paris Sud - Paris XI, 2005. Français. ⟨tel-00429497⟩



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