Cell Adhesion Molecules 300107
Cell Adhesion Molecules 300107
Cell Adhesion Molecules 300107
Reconstruction of skin from a suspension of skin cells from a 15-day embryonic mouse. (A)
Section through intact embryonic skin, showing epidermis, dermis, and primary hair follicle. (B)
Suspension of single skin cells from both the dermis and the epidermis. (C) Aggregates after
24 hours. (D) Section through an aggregate, showing migration of epidermal cells to the
periphery. (E) Further differentiation of aggregates (72 hours), showing reconstituted
epidermis and dermis, complete with hair follicles and keratinized layer.
Differential cell affinity hypothesis
Cells A & B have different patterns of molecules on their surfaces and hence
differences strengths of adhesion.
Different cadherins are expressed on different tissues both in the adult and in
the embryo. For example,
• E-cadherin: on all mammalian embryos, in adults restricted to epithelia
• P-cadherin: on placenta, sticks placenta to uterus.
• N-cadherin: on cells of developing nervous system- is first seen on mesodermal
cells in the gastrulating embryo as they lose their E-cadherin expression.
• R-cadherin: critical in formation of the retina
• B-cadherin: on many nerual structures
• EP-cadherin (C-cadherin): maintains adhesion between the blastomeres of the
Xenopus blastula and is required for the normal movements of gastrulation
• Protocadherins differ from the classic cadherins by lacking connections to the
cytoskeleton through catenins. Are very important in separating the notochord
from the other mesodermal tissues during Xenopus gastrulation.
Cadherins can engage in homophilic adhesion, or Different cadherins may bind
to each other - strength of cadherin-cadherin binding that mediates formation
of many embryonic structures.
Cadherins
Cadherins can engage in homophilic adhesion, or different cadherins may bind to
each other.
- strength of cadherin-cadherin binding is determined by both the quantity and
type of cadherin expressed.
Fibronectin
and amphibian
gastrulation.
(A) Immunofluorescence reveals a network of fibronectin on the basal surface of the prospective
ectodermal cells lining the blastocoel roof in the salamander embryo. Scanning electron
micrographs of normal (B, C) and abnormal (D, E) salamander gastrulation. The blastocoel in (D)
and (E) was injected with the cell-binding fragment of fibronectin (RGD). (B) Section during mid-
gastrulation. (C) The yolk plug toward the end of gastrulation. (D, E) Final stages of arrested
gastrulation: the mesodermal precursors, having bound RGD peptides, cannot recognize the
normal fibronectin-lined migration route. The archenteron fails to form, and the noninvoluted
mesodermal precursors remain on the surface. (A from Boucaut et al. 1985; B-E from Boucaut et
al. 1984)
IgCAMs
Ig-superfamily includes over 100
members many of which are cell
Fig (B) N-CAM
recognising adhesion molecules. All have one or
another N-CAM more immunoglobulin (Ig)-like domain.
molecules on a
different cell • Ig-like domains are β-sheets stabilised
(homophilic by di-sulphide bonding.
ligand).
• Ig domains are resistant to proteases
and are adaptable for the presentation
of recognition domains.
• FNIII repeat, in most IgCAMs, is a ~90 amino acid motif
related to domains in fibronectin
• IgCAMs recognise both homophilic and heterophilic ligands.
• Integrins are frequently heterophilic ligands for Ig-
superfamily members, e.g. ICAM binds to β2-integrins on
blood cells;
• Ca++ dependence for ligand binding is variable.
• N-CAM is the most abundant Ca++ -independent cell-cell
adhesion molecule in vertebrates.
IgCAMs
• N-CAM exists in multiple isoforms generated by
alternative splicing of an RNA transcript from one
gene.
• N-CAM180: neurons late in development,
• N-CAM140: on neurons and glia, mediates neurite
outgrowth (on migratory growth cones & axon shafts of
developing neurons)
• N-CAM120: predominantly on glial cells.
A. Before hatching
little L-selectin
expression on human
trophoblast, B & C.
After hatching bright Cytotrophoblast cells adhere to
L-selectin staining. D. endometrial biopsies and stain with
Phase contrast L-selectin (A & B). Adhesion was
image of C. blocked with a mAb directed against
L-selectin (C - F). Controls C & E;
with mAb D & F.
Collective cell migration: cells keep their cell-cell contacts and migrate as
chords or strands into the tissues.
→both cell-cell adhesion and cell-matrix adhesion, strength of both types of
adhesion need to be balanced for movement of the cell cluster.
Collective cell migration
Single Cell movement requires:
• an interaction with the substrate
via adhesion molecules (integrins)
binding extracellular matrix
proteins
• cell extensions (lamellipodia)
propelled by actin polymerisation in
the cell cortext,
• shortening of membrane tethered
actin filaments causes cell
contraction and
• retraction of the rear of the cell
relaxes the tension caused by
extension of the lamellipodia.
• focal contacts may be resolved at the trailing edge by affinity modulation of
integrins → in migrating cells focal adhesions are dynamic structures that are
constantly being remodeled in size and shape.
Collective cell migration
β1 & β3 integrins
cluster at ruffling
edges.
Leading cells
generate actin and
integrin-mediated
traction.
Cadherin mediated
cell-cell adhesion
with IgCAMs aiding from Friedl et al. 2004 Int. J. Dev. Biol. 48:441
in interactions →
a cortical actin network extends along cell-cell junctions into the cell cluster.
Shortening of membrane tethered actin filaments causes the cell cluster to
retract.
Surface proteases (members of the MMP family) execute local proteolysis →
space for forward moving cell body to penetrate ECM scaffolds.
For cell detachment integrins are either released into the matrix or
internalised following affinity modulation which decreases adhesion.
Collective cell migration