Plasticity versus specificity in RTK signalling modalities for distinct biological outcomes in motor neurons

N Caruso (1) , B Herberth (1) , F Lamballe (1) , V Arce-Gorvel (2) , F Maina (1) , F Helmbacher (1)

1 IBDM - Institut de Biologie du Développement de Marseille
2 CIML - Centre d'Immunologie de Marseille - Luminy

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 is 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 in 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 us to uncouple 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. CONCLUSIONS: 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.

Domaines: Biologie cellulaire

N Caruso, B Herberth, F Lamballe, V Arce-Gorvel, F Maina, et al.. Plasticity versus specificity in RTK signalling modalities for distinct biological outcomes in motor neurons. BMC Biology, 2014, 12 (1), pp.56. ⟨10.1186/s12915-014-0056-6⟩. ⟨hal-01101640⟩