research / Axon guidance

Axonal Pathway selection

Dorsoventral motor guidance by EphA/EphrinA and GDNF/Ret signaling

Establishment of the topographic innervation of limb muscles by motor neurons involves as series of binary decision between two alternative axonal trajectories, during which growth cones of each motor neuron subtype evaluate peripheral signals and chose their appropriate trajectory to reach their specific muscle target. We have shown earlier that the EphA4 tyrosine kinase receptor played an essential role in motor axon pathway selection in the limb (Helmbacher et al., 2000). We have recently shown that GDNF and its receptor Ret participate to the same axon guidance decision. In gdnf or ret mutant mice, LMC(l) axons follow an aberrant ventral trajectory away from dorsal territory enriched in GDNF, while ectopic expression of Ret in chicken embryos is sufficient to reroute LMC(m) axons dorsally. The Ret-loss-of-function phenotype is enhanced in mutant mice lacking Ret and EphA4. Thus, Ret and EphA4 cooperate to enforce the precision of the same binary choice in motor axon guidance.

Reference publications:

-Kramer E*; Knott L*; Su F; Dessaud E; Krull CE; Helmbacher F*, and Klein R*. (2006). Cooperation between GDNF/Ret and ephrinA/EphA4 signals for motor axon pathway selection in the limb. Neuron 50, 35-47. (*These authors contributed equally to the work).

Kramer 2006 (pdf, 1038 Ko)

-Helmbacher, F., Schneider-Maunoury, S., Topilko, P., Tiret, L. and Charnay, P. (2000). Targeting of the EphA4 tyrosine kinase receptor affects dorsal/ventral pathfinding of limb motor axons. Development127, 3313-24.

Helmbacher 2000 (pdf, 446 Ko)


Novel players in axon guidance ?

We have selected genes expressed in subpopulations of motor neurons. Among them we are currently studying the roles, possibly as new players in axon guidance, of transmembrane molecules or their signalling effectors.

Latest news:
We are proud to announce the recent publication of work from our collaborators in the Fadel Tissir Laboratory in Louvain, who identified Celsr3 and Frzd3 as novel players in the field of dorso-ventral pathway selection, through a novel mechanism. To steer LMCl axons dorsally, Celsr3 and Frzd3 signal in a Vangl2-independent way, but instead, bind EphrinAs in cis, and are required to mediate the reverse signaling response to attractive EphAs sent by the dorsal limb compartment.

Chai G, Zhou L, Manto M, Helmbacher F, Clotman F, Goffinet AM, Tissir F. Celsr3 is required in motor neurons to steer their axons in the hindlimb. Nature Neuroscience (2014); doi:10.1038/nn.3784

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last updated 28.06.2015