Cell Adhesion and Cell Sorting
Cell Identity
?
Morphogenesis
Cell Biology
Cell Division/Death
Cell Adhesion
Cell Movement
Cell Shape
Cells Can Have Different Degrees of Contact
(Adhesion) to Their Neighbors
Epithelia: Tight adhesion, clear cell-cell junctions, highly ordered
Mesenchyme: Loose adhesion but still contiguous tissue
Individual cells
Cell Movements Relevant for Gastrulation
Getting cells inside
Spreading tissues out
Moving cells around
Making tissues longer
Convergence/extension
Cell Adhesion Can Also Control Cell Sorting
H. panicea
H. panicea
M. prolifera
M. prolifera
Fernandez-Bisquets amd Burger
Dissociate sponge through silk sieve
Allow cells to reaggregate (requires calcium)
Cells sort out to make new sponges in species-specific manner
Embryonic Cells Exhibit Spontaneous Cell Sorting Ability
Townes and Holtfreter, 1955
Cells of a particular IDENTITY can have affinity for one another
This affinity can cause them to sort out in predictable ways
Amphibian Gastrulation Normally Results From
Precisely Controlled Cellular Movements
“Gastrulation” By Cell Sorting in Dissociated Embryos!
Townes and Holtfreter, 1955
Differential Adhesion Hypothesis:
Cells rearrange so as to maximize adhesive interactions
Weakly adhering cells will sort outside or spread over
strongly adhering cells
Requires differential cell adhesion and cell motility
Malcolm S. Steinberg
More P-cadherin
Less P-cadherin
Minus calcium
LOW HIGH
Townes and Holtfreter, 1955
Cell Sorting in the Embryonic Mesoderm in Drosophila
1) A/P and D/V info to
specify cell identity
2) Cell sorting to make
contiguous tissues
Cell Sorting in the Neural Crest
and in Somite Derivatives
(Dermis)
(Muscle)
(Vertebrae)
Functional Classes of Cell Adhesion Molecules
(CAMs)
Cell-cell vs. Cell-ECM
Junctional vs. non-junctional
Homophillic vs. heterophillic
Calcium dependent vs. independent
Types of Cell Adhesion
apical
adherens junction
baso-lateral
ECM (collagen, fibronectin, laminin, etc.)
Types of Cell Adhesion
Epithelium
Mesenchyme
Integrins
-Primarily Cell-ECM
(but sometimes Cell-Cell)
-Calcium Dependent
-Heterodimeric--different dimers
can have different ligands
Ig-CAMs
-Cell-cell (but some bind ECM)
-”Immunoglobulin like” extracellular domains
- Heterophillic or homophillic
-Calcium Independent
-Many expressed in nervous system
-865 members in human genome???
N-CAM Forms
Cadherins
-Cell-cell
-Primarily homophillic
-Calcium Dependent
Cell Adhesion Molecules and Signaling
Modulation of
Growth Factor
Response
Sensing CellCell Contact
Sensing
Mechanical Strain
(Tension, Substrate
Rigidity, Flow)
Activation by
Cleavage
PMID:21346732
The Notch Pathway: Cell-cell adhesion as a signal
Cleavage and “Shedding” of N-Cadherin Ectodomain by ADAM10
Reiss et al. EMBO 2005
Anti-N-cad
Regulation of Transcription by N-Cadherin Intracellular Domain
Marambaud et al. Cell 2003
N-Cad CTF Binds CBP
N-Cad CTF inhibits CREB-dependent Txn
Blocking Secretase Activates CREB-depd Txn
How are Cell Adhesion and CAMs Regulated?
Production (transcription, splicing, RNA stability, translation)
Post-Translational Modification (phosphorylation, glycosylation)
Subcellular Localization (Cell Surface Localization, Endocytosis)
Protein-Protein Interaction (adhesion complex members)
Connection to the cytoskeleton
Proteolytic Cleavage
61 kb just for transcription unit!
12 x 48 x 33 x 2= 38,016 possible splice forms!!!
RT-PCR and sequence 50 cDNA clones:
49 different combinations of Exons 4, 6 and 9!!
Alternative splicing can create a larger repertoire of CAM binding specificities
What Do Cell Adhesion and CAMs Regulate?
Cell Proliferation (contact inhibition)
Cell Death
Cell Shape
Cell Migration
Cell Identity
Cell Sorting
Tissue Type (epithelial vs. mesenchymal)
Tissue Organization/Shape
The Fat/Ds Cadherins Regulate Tissue Size Via the Hippo Pathway
PMID:21138973
Cell-ECM and Cell-Cell Adhesion is Essential for Cell Migration
Proper strength of adhesion is critical for migration:
too much can be as bad as too little
The Epithelial-to-Mesenchymal
Transition (EMT)
Gastrulation
Neural Crest Emmigration
Takeichi…Uemura 2000
Nieto, 2002
Somite
Development
Gastrulation
(EMT)
MET
EMT
Cell Adhesion Regulates Planar Cell Polarity
PCP
Apical
Basal
Cadherins are also
important for Planar
Cell Polarity
Classical cadherins
are important for
Apical-Basal Polarity
wt
Dsh
Uemura and colleagues
flamingo
gain of function
Flamingo
Planar Cell Polarity and the Mammalian Organ of Corti (Inner Ear)
Stereocillia Bundles
Mouse flamingo-
Origins of Multicellularity: Adhesion is not just for animals
Candida Hyphae
Bacterial Biofilms
Fungi
Plants
Dictyostelium
Social Development in Dictyostelium
Migration as single cells
Morphogenesis and “fruiting body” formation
Motile aggregate (slug)
Origins of Multicellularity: Evolution of adhesion
Increased Diversity of
Cell Junctions
Diploblasts
(no mesoderm)
Sponge
Choanoflagellate
Sponge genome Aug 2010 PMID: 20686567
Multicellular
Classical Cadherins
Par proteins
Unicellular
Cadherin families
No “Classical” Cadherin
Catenins
Single and multi-cellular phases
“Polarized Epithelia”
Catenins
No Cadherins
EMT and Cancer Progression and Metastasis
Lose E-cad
E-cad can be
re-expressed
Transition from Adenoma to Carcinoma is
correlated with loss of E-cadherin
E-cad supresses, and Dominant Negative E-cad enhances, tumor progression and metastasis
Pancreatic Cancer Model
(Increased wt E-cad)
(Increased DN E-cad)
*
*Note: Carcinomas had lost E-cad expression
E-cadherin is a Tumor Suppressor Gene
Somatic mutations
Germline mutations
PMID:20457567