research / Motor Neuron pool specification / Effectors of MN subtype identity


Effectors of the PEA3 neuronal identity



identification of targets of PEA3 and Met signaling in PEA3 neurons


We have used different approaches to identify transcriptional targets of PEA3 and/or Met signaling. Most candidates obtained have been selected for their selective expression in subsets of the PEA3 domain, and for their requirements on Met and PEA3 for this expression. We are currently studying the functions of these molecules.



wild type

met mutants

example
candidate




Example of a molecule found to be target of HGF/Met in the Met/Pea3+ motor neurons. Its expression is shown by in situ hybridization on wild type (left) and met-/- (right) brachial spinal cords. its expression in these neurons is abolished in met mutants, indicating that this molecule is a target of HGF/Met signaling.


Molecules involved in target muscle innervation


We are looking for transcriptional tagets of PEA3 that may control the selective trajectory in the periphery taken by axons of the PEA3-positive neurons to reach their target muscles (latissimus dorsi, cutaneus maximus)

We currently focus on several membrane molecules of the protocadherin family, that were found to be expressed in subsets of PEA3 neurons and which expression is dependent on PEA3 functions


Survival of PEA3 motor neurons


The phenomenon of recruitment of motor neurons to the PEA3 population is triggered by the cooperative action of two limb-derived growth factors, GDNF and HGF, which are also known survival factors for motor neurons. Thus, the strategies that are undertaken to identify molecules playing a role in this motor neuron specification event are also expected to lead to the identification of molecular effectors of the survival-promoting actions of GDNF and HGF. The capacity of HGF and GDNF to reduce the severity of mouse models of motor neuron diseases is currently the focus of intense effort. The characterization of their downstream targets in motor neurons will thus contribute to improving the design of therapies for pathologies of the motor neuron such as ALS (Amyotrophic lateral sclerosis) and/or SMA (spinal muscular atrophy).


Genestine M., Caricati E., Fico A., Richelme S., Hassani H., Lamballe F., Panzica G., Pettmann B., Helmbacher F., Raoul C., Maina F.* and Dono R.*. (2011). Enhanced neuronal Met signalling levels in ALS mice delay disease onset. Cell Death Dis. 2011 Mar 17;2:e130. PMID: 21412276


Like GDNF, HGF is known  for its capacity to promote motor neuron survival in vitro. Pool-specific expression of Met, the receptor for HGF, argues in favor of the idea of pool specific control of Motor Neuron survival by HGF. However, evidence for this was so far still lacking, in part because the HGF/Met system has pleiotropic functions, and several of these functions indirectly impact of muscle biology, such as its role for muscle migration to the limb, or its early actions of motor axon growth/pathfinding or on motor neuron specification. Taking advantage of a conditional mouse mutant for met, and a system enabling excision of the gene not only specifically in the nervous system, but also bypassing the early neural functions, we were able to delete Met in the nervous system at a timing relevant to evaluate its contribution to the control of motor neuron numbers. We have shown that Met is specifically required to support the survival of one motor pool, specifically innervating one muscle, the pectoralis minor. Interestingly, HGF/Met were not required at earlier stages for axon growth of this motor pool. Instead, we showed that Met functions were dispensible in two other motor pools in which Met functions were required for specification or axon growth at earlier stages. This illustrates to an exquisite degree to which outcomes of signaling by receptor tyrosine kinases are regulated on a cell-by-cell basis. They also provide a model for one way in which the multiplicity of neurotrophic factors may allow for regulation of MN numbers in a pool-specific manner.


F. Lamballe, M. Genestine, N. Caruso, V. Arce, S. Richelme, F. Helmbacher*, F. Maina*. (2011). Pool-specific regulation of motor neuron survival by neurotrophic support. J. Neurosci. 2011, Aug 3;31(31):11144-58. PMID:21813676. (*co-last and co-corresponding authors).



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last updated 28.06.2015