Biology Reference
In-Depth Information
NCAM-Fc or L1-Fc chimaeras stimulates outgrowth as strongly as do cell-surface NCAM or
L1: direct stimulation of FGFR by FGFs has the same effect.
25
Observations like this challenge
the whole concept of what a 'cell adhesion molecule' is. The first member of each adhesion
molecule family was generally identified in screens for monoclonal antibodies that pre-
vented, for example, fasciculation of neurites in culture. This was naturally assumed to reflect
a failure of growth cones to adhere to axons, which in a sense it was, but it is now clear that at
least part of this effect must have been due to changes in the abilities of growth cones to navi-
gate by sensing the chemical properties of their surroundings. The balance of mechanical
adhesion and signalling in most systems is not clear, and will not be until much more
research has been done. Until then, it would be wise to treat the term 'adhesion molecule'
like the term 'growth factor'
d
a phrase that is appropriate for how the first members of these
protein families were identified, but that is not necessarily the best description of their main
function
in vivo
.
PATHW
AYS OF ATTRACTIVE MOLECULES IN THE E
MBRYO
The predilection of cells for substrates that encourage cell-substrate adhesion can be used
to guide migration in the embryo (wherever the balance between the mechanisms of hapto-
taxis and signal transduction lies). Neural crest cells of vertebrates migrate from the dorsal
part of the neural tube and, in the trunk, follow two main pathways at first, travelling either
ventromedially, close to the neural tube, or dorsolaterally under the skin. Both pathways are
rich in components of the extracellular matrix, including fibronectin, laminin and a few
dozen others,
27
suggesting that they form tracks along which migratory cells are meant to
travel. Antibodies that interfere with the adhesion of neural crest cells to the matrix reduce
crest cell migration markedly,
28
as do antisense oligonucleotides that inhibit the expression
of integrin receptors for these matrix components.
29
On the other hand, implanting artificial
membranes containing large quantities of fibronectin into embryos of the axolotl
Ambystoma
mexicanum
greatly stimulates outgrowth of neural crest cells along the artificial membranes.
30
One way in which adhesive substrates are used all over the body and across a great range
of phyla is in the construction of nerves from individual axons. Nerves are constructed by the
process of fasciculation, in which growth cones choose to migrate along existing axons in
preference to making their own way across the surrounding substrate. Existing axons are
attractive to growth cones because they express cell adhesion molecules such as NCAM
and L1, which will bind to the same type of molecule on the growth cone.
31
L1 is expressed
in many fibre tracts and is required for their formation; antibodies to L1 reduce fasciculation
in cultured embryonic cerebelum,
32
and mouse and human mutants lacking L1 function
show severe disruption to CNS development.
33
Similarly, NCAM is expressed in the mossy
fibre tract, a large trunk of fasciculated axons in the mammalian hippocampus, as it forms. In
the absence of NCAM function, the fasciculation of these axons fails.
34
In the densely packed
neural tissue of the central nervous system, there are many fibre tracts that head in different
directions to different destinations. A growth cone is therefore faced with the problem of
joining exactly the right tract and ignoring the distractions of others that may lie in its
path. In the CNS of insects, different fibre tracts express adhesive proteins so that pathways
may be labelled uniquely. In the grasshopper
Schistocerca americana
and in the fruitfly
