Presynaptic Differentiation Factors

The laminins bind to presynaptic proteins and mutations in laminin genes cause defects in presynaptic differentiation. However, these mutations do not cause a total failure of the motor axon to stop and differentiate. Interestingly, the only mutations where a nearly complete failure in presynaptic differentiation is seen are mice lacking agrin or MuSK, or even rapsyn, all proteins primarily implicated in postsynaptic differentiation. Agrin can serve directly as a signal for stopping neurite outgrowth and presynaptic differentiation in vitro59~61. However, in mutant mice that lack only the alternatively spliced "active" Z exons and express normal levels of muscle agrin, the presynaptic overgrowth phenotype is still present and is as severe as the null allele of agrin12. This suggests that agrin in the muscle ECM is not directly responsible for presynaptic differentiation of motor-nerve terminals in vivo. Indeed, the possibility of rapsyn, an intracellular scaffolding protein, interacting directly with nerve terminals is unlikely. Therefore, the conclusion to be reached is that presynaptic differentiation fails in these mutant mice secondary to the failure of postsynaptic differentiation. Presumably, a retrograde signal (or signals) that is generated in the muscle is no longer produced when the agrin-signaling pathway is perturbed.

While the laminins may be contributing components to this presynaptic differentiation signal, they are clearly not the only components. Furthermore, it is not clear whether this signal is a diffusible factor acting non-cell-autonomously, or an adhesion molecule acting directly on individual nerve terminals and muscle fibers, or a combination of such factors.

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