Figure 1

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 (Met^WT) 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 Met^2P and Met^2S have been designed to carry optimal binding sites for PI3K and Src, so as to favour their respective recruitment/activation [9]. The Met^d receptor has its two tyrosines replaced by phenylalanines and is thus signalling incompetent [9],[15]. As a consequence, met^d/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 [4],[16]. 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[4] and non-cell autonomous propagation of Pea3-expression [16]. 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.