research / Motor Neuron pool specification / Pool specific control of MN survival


Pool-specific control of Motor Neuron survival



Trophic factors and motor neuron survival


2014


Background: Multiple growth factors are known to control several aspects of neuronal biology, consecutively acting as morphogens to diversify neuronal fates, as guidance cues for axonal growth, and as modulators of survival or death to regulate neuronal numbers. The multiplicity of neuronal types is permitted by the combinatorial usage of growth factor receptors, each of which being expressed in distinct and overlapping subsets of neurons, and by the multitasking role of growth factor receptors, which recruit multiple signalling cascades differentially required for distinct biological outcomes. We have explored signalling robustness in cells where a given receptor tyrosine kinase (RTK) elicits qualitatively distinct outcomes. As the HGF/Met system regulates several biological responses on motor neurons (MN) during neuromuscular development, we have investigated the signalling modalities through which the HGF/Met system impacts on MN biology, and the degree of robustness of each of these functions, when challenged with substitutions of signalling pathways.
Results: Using a set of mouse lines carrying signalling mutations that change the Met phosphotyrosine binding preferences, we have asked whether distinct functions of Met in several MN subtypes require specific signalling pathways, and to which extent signalling plasticity allows a pleiotropic system to exert distinct developmental outcomes. The differential ability of signalling mutants to promote muscle migration versus axonal growth allowed uncoupling an indirect effect of HGF/Met signalling on nerve growth through the regulation of muscle size from a direct regulation of motor growth via the PI3 kinase (PI3K), but not Src kinase, pathway. Furthermore, we found that HGF/Met-triggered expansion of Pea3 expression domain in the spinal cord can be accomplished through several alternative signalling cascades, differentially sensitive to the Pea3 dosage. Finally, we show that the regulation of MN survival by HGF/Met can equally be achieved in vitro and in vivo by alternative signalling cascades involving either PI3K-Akt or Src and Mek pathways.
Conclusion: Our findings distinguish MN survival and fate specification, as RTK-triggered responses allowing substitutions of the downstream signalling routes, from nerve growth patterning, which depends on a selective, non-substitutable pathway


Publication:

Caruso N., Herberth B., Lamballe F., Arce-Gorvel V., Maina F., and Helmbacher F. Plasticity versus specificity in RTK signalling modalities for distinct biological outcomes in motor neurons. BMC Biology 2014, 12:56 doi:10.1186/s12915-014-0056-6



Figure 7: Summary of the signaling modalities characterizing each of the functions of HGF/Met in MNs. (A, B) Schematic summary of the MN populations in which HGF exerts its functions, highlighting which subsets express Met. (A) Scheme representing the three subsets of Pea3-expressing MNs, and the mechanism by which GDNF and HGF cooperate to establish Pea3 expression domain: GDNF acts on Ret/GFRa1 expressing “pioneer” neurons (dark blue pool, believed to largely match the CM MN pool) , to induce Pea3 expression. Pea3 in turn is required to induce expression of the HGF receptor Met. HGF acts on the same “pioneer” neurons, once they express Met, to trigger the production by these neurons of a signal (referred to as X) that induces Pea3 expression in additional neurons (“recruited”). This leads to the lateral enlargement of the CM pool (within which Met expression propagates as well), and to the recruitment of more anterior neurons (red, largely matching the LD MN pool), which will not express Met. (B) Scheme representing lumbar axonal MN projects in the hindlimb, with colours distinguishing Met-dependent from Met-42 independent guidance. (C) Summary table of the various biological aspects of neuromuscular development involving HGF/Met.

Caruso BMC Biol 2014 (pdf 3.1Mb)

   


2011


The precise control of motor neuron  death and survival following initial innervation of skeletal muscle targets is a key step in sculpting a functional motor system, but how this is regulated at the level of individual motor pools remains unclear. HGF is known  for its capacity to promote motor neuron survival in vitro, and expression of its receptor, Met, in discrete subsets of motor neurons, 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. Several functions of HGF/Met that 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, had precluded investigating the direct involvement in pool-specific control of motor neuron survival. 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 the 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).


Work done in collaboration with Flavio Maina's team


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



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