1. ? Cell Biology Cell Division/Death Cell Adhesion Cell Movement Cell Shape Cell Adhesion and Cell Sorting Cell Identity Morphogenesis

2. 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

3. Moving cells around Spreading tissues out Making tissues longer Convergence/extension Cell Movements Relevant for Gastrulation Getting cells inside

4. Cell Adhesion Can Also Control Cell Sorting H. panicea M. prolifera H. panicea 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

5. 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

6. Amphibian Gastrulation Normally Results From Precisely Controlled Cellular Movements

7. “Gastrulation” By Cell Sorting in Dissociated Embryos! Townes and Holtfreter, 1955

8. 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

9. More P-cadherin Less P-cadherin Minus calcium LOWHIGH

10. Townes and Holtfreter, 1955

13. 2) Cell sorting to make contiguous tissues Cell Sorting in the Embryonic Mesoderm in Drosophila 1) A/P and D/V info to specify cell identity

14. and in Somite Derivatives (Dermis) (Muscle) (Vertebrae) Cell Sorting in the Neural Crest

15. Functional Classes of Cell Adhesion Molecules (CAMs) Cell-cell vs. Cell-ECM Junctional vs. non-junctional Homophillic vs. heterophillic Calcium dependent vs. independent

16. Types of Cell Adhesion apical adherens junction baso-lateral ECM (collagen, fibronectin, laminin, etc.)

17. Types of Cell Adhesion Epithelium Mesenchyme

18. Integrins -Primarily Cell-ECM (but sometimes Cell-Cell) -Calcium Dependent -Heterodimeric--different dimers can have different ligands

19. Ig-CAMs N-CAM Forms -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???

20. Cadherins -Cell-cell -Primarily homophillic -Calcium Dependent

21. Cell Adhesion Molecules and Signaling Modulation of Growth Factor Response Sensing Cell-Cell Contact Sensing Mechanical Strain (Tension, Substrate Rigidity, Flow) Activation by Cleavage PMID:21346732

22. The Notch Pathway: Cell-cell adhesion as a signal

23. Anti-N-cad Cleavage and “Shedding” of N-Cadherin Ectodomain by ADAM10 Reiss et al. EMBO 2005

24. Regulation of Transcription by N-Cadherin Intracellular Domain N-Cad CTF Binds CBP Blocking Secretase Activates CREB-depd Txn N-Cad CTF inhibits CREB-dependent Txn Marambaud et al. Cell 2003

25. 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

26. 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

27. 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

28. The Fat/Ds Cadherins Regulate Tissue Size Via the Hippo Pathway PMID:21138973

29. 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

30. The Epithelial-to-Mesenchymal Transition (EMT) Gastrulation Neural Crest Emmigration Takeichi…Uemura 2000 Nieto, 2002

31. MET EMT Somite Development Gastrulation (EMT)

32. flamingo gain of function wt Dsh Flamingo Uemura and colleagues 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

33. Planar Cell Polarity and the Mammalian Organ of Corti (Inner Ear) Stereocillia Bundles Mouse flamingo-

34. Origins of Multicellularity: Adhesion is not just for animals Candida Hyphae Fungi Bacterial Biofilms Plants Dictyostelium

35. Social Development in Dictyostelium Migration as single cells Morphogenesis and “fruiting body” formation Motile aggregate (slug)

36. Origins of Multicellularity: Evolution of adhesion Increased Diversity of Cell Junctions Multicellular Classical Cadherins Par proteins Diploblasts (no mesoderm) Sponge Choanoflagellate Unicellular Cadherin families No “Classical” Cadherin Catenins Single and multi-cellular phases “Polarized Epithelia” Catenins No Cadherins Sponge genome Aug 2010 PMID: 20686567

37. EMT and Cancer Progression and Metastasis Lose E-cad E-cad can be re-expressed

38. 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 * *Note: Carcinomas had lost E-cad expression (Increased wt E-cad) (Increased DN E-cad)

39. E-cadherin is a Tumor Suppressor Gene Somatic mutations Germline mutations

40. PMID:20457567