Using Met specificity-switch mutants to study plasticity of HGF/Met functions in motor neurons. (A) The wild type (WT) and three signalling mutant versions of the Met receptors used in this study. The WT receptor (MetWT) conveys intracellular signalling mainly through two tyrosine residues located in the C-terminal tail. Upon HGF binding and phosphorylation by the Met kinase domain, these tyrosines recruit several cytoplasmic signalling effectors, including Gab1, PI3K, Src, Grb2 and a number of others. The specificity-switch mutants Met2P and Met2S have been designed to carry optimal binding sites for PI3K and Src, so as to favour their respective recruitment/activation . The Metd receptor has its two tyrosines replaced by phenylalanines and is thus signalling incompetent ,. As a consequence, metd/d embryos have phenotypes indistinguishable from null mutants. (B) Time course of developmental events regulated by HGF/Met signalling that influence MN biology, summarising our earlier findings ,. The period shown is divided into an early period, from E10.5 to E13.5, before synaptic contact between MNs and muscles, and a late period, during which MNs are dependent on muscle-derived trophic factors for their survival. The transition between the two periods is marked by a pronounced peak of MN death (NOCD), indicating numerical adjustment of MN numbers to target muscle size. During the muscle-independent period, before NOCD, HGF/Met signalling controls migration of limb myoblasts, axon growth of a subset of Met-expressing MNs, cell autonomous induction of runx1 and non-cell autonomous propagation of Pea3-expression . After NOCD, HGF/Met controls the survival of a distinct pool of MNs, innervating the pectoralis minor muscle, while it is no longer required for trophic support of CM or latissimus dorsi (LD) MN pools.