Biomedical subjects

Céline Ménager

Publications and source records attributed to Céline Ménager.

4 recordsLinked to original sources

PubMed2005

Phosphorylation by Rho kinase regulates CRMP-2 activity in growth cones.

Collapsin response mediator protein 2 (CRMP-2) enhances the advance of growth cones by regulating microtubule assembly and Numb-mediated endocytosis. We previously showed that Rho kinase phosphorylates CRMP-2 during growth cone collapse; however, the roles of phosphorylated CRMP-2 in growth cone collapse remain to be clarified. Here, we report that CRMP-2 phosphorylation by Rho kinase cancels the binding activity to the tubulin dimer, microtubules, or Numb. CRMP-2 binds to actin, but its binding is not affected by phosphorylation. Electron microscopy revealed that CRMP-2 localizes on microtubules, clathrin-coated pits, and actin filaments in dorsal root ganglion neuron growth cones, while phosphorylated CRMP-2 localizes only on actin filaments. The phosphomimic mutant of CRMP-2 has a weakened ability to enhance neurite elongation. Furthermore, ephrin-A5 induces phosphorylation of CRMP-2 via Rho kinase during growth cone collapse. Taken together, these results suggest that Rho kinase phosphorylates CRMP-2, and inactivates the ability of CRMP-2 to promote microtubule assembly and Numb-mediated endocytosis, during growth cone collapse.

Animals↗

PubMed2004

PIP3 is involved in neuronal polarization and axon formation.

Recent experiments in various cell types such as mammalian neutrophils and Dictyostelium discoideum amoebae point to a key role for the lipid product of PI 3-kinase, PIP(3), in determining internal polarity. In neurons, as a consequence of the elongation of one neurite, the axon is specified and the cell acquires its polarity. To test the hypothesis that PI 3-kinase and PIP(3) may play a role in neuronal polarity, and especially in axon specification, we observed localization of PIP(3) visualized by Akt-PH-GFP in developing hippocampal neurons. We found that PIP(3) accumulates in the tip of the growing processes. This accumulation is inhibited by addition of PI 3-kinase inhibitors. Those inhibitors, consistently with a role of PIP(3) in process formation and elongation, delay the transition from stage 1 neurons to stage 3 neurons, and both axon formation and elongation. Moreover, when the immature neurite contacts a bead coated with laminin, a substrate known to induce axon specification, PIP(3) accumulates in its growth cone followed by a rapid elongation of the neurite. In such conditions, the addition of PI 3-kinase inhibitors inhibits both PIP(3) accumulation and future axon elongation. These results suggest that PIP(3) is involved in axon specification, possibly by stimulating neurite outgrowth. In addition, when a second neurite contacted the beads, this neurite rapidly elongates whereas the elongation of the first laminin-contacting neurite stops, consistently with the hypothesis of a negative feedback mechanism from the growing future axon to the other neurites.

Animals↗

PubMed2003

[Rho proteins: their function in neurons].

Neurons possess a polarized morphology. In general, each neuron has several dendrites but only one axon. Such morphology is the basis for directionalized rapid signaling, information flowing from the short dendrites to the long axon. The mechanisms involved in the establishment of the neuronal polarity remain largely unknown. However, recently, members of Rho family proteins have been implicated in the regulation of neuronal morphology especially development of neuronal polarity, axon outgrowth and guidance, dendritic tree elaboration and synapse formation. Moreover, the Rho GTPases have been reported to be directly or indirectly involved in some neurological conditions such as X-linked mental retardation as well as Alzheimer's and Parkinson's diseases. These findings demonstrate the importance of Rho GTPases in the development, maintenance and function of the nervous system.

Alzheimer Disease↗

PubMed2002

CRMP-2 binds to tubulin heterodimers to promote microtubule assembly.

Regulated increase in the formation of microtubule arrays is thought to be important for axonal growth. Collapsin response mediator protein-2 (CRMP-2) is a mammalian homologue of UNC-33, mutations in which result in abnormal axon termination. We recently demonstrated that CRMP-2 is critical for axonal differentiation. Here, we identify two activities of CRMP-2: tubulin-heterodimer binding and the promotion of microtubule assembly. CRMP-2 bound tubulin dimers with higher affinity than it bound microtubules. Association of CRMP-2 with microtubules was enhanced by tubulin polymerization in the presence of CRMP-2. The binding property of CRMP-2 with tubulin was apparently distinct from that of Tau, which preferentially bound microtubules. In neurons, overexpression of CRMP-2 promoted axonal growth and branching. A mutant of CRMP-2, lacking the region responsible for microtubule assembly, inhibited axonal growth and branching in a dominant-negative manner. Taken together, our results suggest that CRMP-2 regulates axonal growth and branching as a partner of the tubulin heterodimer, in a different fashion from traditional MAPs.

Animals↗