Biology Reference
In-Depth Information
Development of migrating muscle precursor cells
Muscles of the vertebrate trunk are generated from the dermomyotome, a
derivative of the somite (Christ and Ordahl, 1995). A major subclass of
hypaxial trunk muscles derives from long-range migrating progenitors. These
migrating cells delaminate from the ventro-lateral dermomyotome on
particular axial levels, and move as undifferentiated cells to specific targets
where they form skeletal muscle. In mammals, the cells migrate to the limbs,
the hypoglossal cord and the septum transversum, where they form the
muscles of the extremities, tongue and diaphragm. Critical steps in the
development of the migrating myogenic lineage are (1) the formation and
specification of the precursor pool in the dermomyotome, (2) the delamination
of the precursor cells and their migration to the correct target sites, (3)
proliferation of precursors at their targets, and, finally (4) the activation of the
myogenic programme at the targets by the myogenic regulatory factors. Genes
that control general dermomyotome development or the myogenic
programme have obviously broad roles in muscle development. However,
additional steps are needed to specify development of the migrating lineage.
Indeed, mutations that profoundly affect muscle groups that derive from
migrating precursors, but not other muscles, have been described.
c-Met, its ligand SF/HGF and the Gab1 adaptor
The c-Met receptor tyrosine kinase was identified because of its oncogenic
potential when mutated, and its biochemical properties and signalling capacity
have been extensively studied (for a recent review see Furge et al., 2000). Its
ligand, scatter factor/hepatocyte growth factor (SF/HGF), was characterized
as a factor that dissociates (scatters) cultured epithelial cells, and that
stimulates growth of hepatocytes (Birchmeier and Gherardi, 1998). Biologi-
cally active SF/HGF is a two-chain heterodimer produced by proteolytic
cleavage of an inactive precursor. The larger alpha chain contains four copies
of the kringle domain. The smaller beta chain resembles a typical serine
protease domain, but lacks enzymatic activity. All known biological functions
of SF/HGF are mediated by its interaction with the c-Met tyrosine kinase
receptor. Upon SF/HGF binding, the cytoplasmic tyrosine kinase activity of
the c-Met receptor is increased, and the receptor is phosphorylated on tyrosine
residues. Activation of the signal transduction pathways downstream of c-Met
occurs mainly through the multidocking site, a short sequence motif located
near the C-terminus of the receptor. Two tyrosine residues (Tyr
1349
and
Tyr
1356
) located within the multidocking site are phosphorylated upon ligand
binding, which play a critical role in the recruitment of several signal
