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Contrôle de la prolifération cellulaire et développement du tube neural : régulation de l'expression des acteurs du cycle cellulaire Cycline D1 et CDC25B par le morphogène Shh.

Abstract : During the early steps of spinal cord development, the neural plate located posteriorly invaginates to form the neural groove and progressively closes to give rise to the neural tube in more anterior regions. FGF signalling promotes the continuous development of the posterior nervous system by maintaining a stem zone of proliferating neural progenitors in the caudal neural plate. The progenitors that escape from this region are subjected to dorso-ventral polarising activities in the neural groove, due notably to Sonic Hedgehog (Shh), and some of them start to differentiate in the neural tube. The protein Shh, which is secreted by ventral structures in the groove, controls both the specification and proliferation of ventral neural progenitors. While the molecular mechanisms leading to neuronal specification are quite well known, the molecular bases of the proliferative effect of Shh remain elusive.
In order to understand how Shh can control proliferation in this context we looked for cell cycle regulators that could be target of this pathway in the ventral part of the chick neural tube. We first investigated the expression pattern of D-type Cyclins, because of their role in coupling extra-cellular signals to the cell cycle machinery. We have found that Cyclin D2 is preferentially expressed in the caudal neural plate, whereas Cyclin D1 is present in the ventral neural groove. We demonstrated, by loss- and gain-of-function experiments, that FGF signalling maintains Cyclin D2 in the immature caudal neural epithelium, whereas Shh specifically activates Cyclin D1 in the ventral neural groove.
We next analysed the expression pattern of other cell cycle regulators. Interestingly, we found that the phosphatase CDC25B, which promotes the G2/M transition, is expressed in a spatial and temporal manner that is consistent with its being a target gene of Shh. Thus, CDC25B is expressed asymmetrically in the Hensen's node, in a ventro-dorsally decreasing gradient in the neural groove and also in the posterior part of the developing limb buds. Loss- and gain-of-function experiments demonstrated that Shh positively regulates the expression of CDC25B both in the neural tube and in the limb buds. These data reveal an unexpected developmental link between the Shh pathway and a regulator of the G2/M transition.
To test the relevance of Shh function on the cell cycle regulation we analysed cell cycle parameters after Shh pathway inhibition. The blockade of the Shh signalling pathway leads to an accumulation of the cells in G1 and a default of entry in mitosis. The effects of Shh on the G1 phase can be due to the regulation of Cyclin D1 expression. Accordingly we have demonstrated that the misexpression of Cyclin D1 in the neural tube favours proliferation of neural precursor cells at the expense of differentiation. The function of CDC25B in the neural tube has not yet been related to the function of the Shh pathway at the G2/M transition. Then the importance of Shh-dependent activation of CDC25B in the ventral spinal cord needs further investigations.
All together these results show that two cell cycle regulators, Cyclin D1 and CDC25B, are targets of Shh signalling in the ventral spinal cord. Our evidence suggests that Shh acts positively on proliferation at two different cell cycle phases: G1 progression and G2/M transition. The control of G1 progression may serve to maintain discrete pools of cycling neural progenitors. The significance of the control of the G2/M transition remains to be elucidated. It nevertheless seems clear that, by virtue of its ability to regulate the cell cycle, Shh can coordinate proliferation with the neuronal specification programme in order to impose a pattern in the ventral spinal cord.
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https://tel.archives-ouvertes.fr/tel-00012116
Contributor : Chantal Michel <>
Submitted on : Tuesday, April 11, 2006 - 2:23:08 PM
Last modification on : Friday, October 23, 2020 - 4:57:32 PM
Long-term archiving on: : Monday, September 17, 2012 - 1:31:04 PM

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Bertrand Benazeraf. Contrôle de la prolifération cellulaire et développement du tube neural : régulation de l'expression des acteurs du cycle cellulaire Cycline D1 et CDC25B par le morphogène Shh.. Biochimie [q-bio.BM]. Université Paul Sabatier - Toulouse III, 2005. Français. ⟨tel-00012116⟩

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