Cell-Cell Communication and Morphogenesis

Introduction to Morphogenesis

  • Morphogenesis: The intricate process involving the construction of organized form within an organism.

  • Development is a complex interplay that extends beyond mere cell differentiation, requiring cells to be meticulously ordered, to create distinct shapes, and to establish specific connections for tissue and organ formation.

Cell-Cell and Cell-Extracellular Matrix Interactions: Foundations of Form
Cell Adhesion and Sorting: The Physics of Morphogenesis

  • How separate tissues are formed: A fundamental question in developmental biology is how cells of a particular type (e.g., bone cells) aggregate and adhere exclusively to other cells of the same type, rather than mixing indiscriminately with adjacent, different cell types (e.g., muscle cells).

  • Differential Cell Affinity (Figure 4.3, 4.4):

    • Experiments involving the reaggregation of dissociated cells from amphibian neurulae demonstrate that different cell types sort out into their own specific regions.

    • Cells not only reaggregate but also reconstruct their original spatial relationships, indicating a selective affinity among cells.

    • Examples of sorting (Figure 4.4):

      • When mixed, epidermis sorts to the exterior, while mesoderm and neural plate cells internalize.

      • In complex mixtures (e.g., epidermis, neural plate, axial mesoderm, endoderm), cells sort into nested layers, mimicking their embryonic positions: endoderm (innermost), neural plate, mesoderm, and epidermis (outermost).

The Differential Adhesion Hypothesis and Cadherins

  • Thermodynamics Model of Cell Interactions / Differential Adhesion Hypothesis (Figure 4.5):

    • This model proposes that cells sort based on differences in their surface tension, which reflects their adhesive properties.

    • Cells with higher surface tension (less adhesive, less cohesive) tend to move to the periphery of aggregates.

    • Cells with lower surface tension (more adhesive, more cohesive) tend to migrate to the interior.

    • This creates a hierarchy of cell sorting mediated by decreasing surface tensions, driven by the system seeking to achieve the most thermodynamically stable configuration (i.e., minimal surface energy).

  • Cadherins (Calcium-Dependent Adhesion Molecules) (Figure 4.6):

    • Cadherins are the primary cell adhesion molecules mediating cell-cell binding.

    • They are anchored inside the cell membrane by a complex of proteins called catenins, which connect cadherins to the cell's cytoskeleton.

    • Different types of cadherins contribute to tissue specificity:

      • E-cadherin: Predominantly found in epithelial cells.

      • P-cadherin: Expressed in placental cells.

      • N-cadherin: Found in neural cells.

      • R-cadherin: Specific to retinal cells.

      • Protocadherin: Another class of cadherins with diverse roles.

  • Importance of Cadherin Amount for Morphogenesis (Figure 4.8):

    • The quantity of cadherin expressed on the cell surface, not just its type, is crucial for cellular sorting and therefore correct morphogenesis.

    • Cells expressing higher levels of a particular cadherin tend to sort to the center of an aggregate.

    • For instance, green cells with 2.4 times more N-cadherin than red cells will sort to the center, pushing red cells to the periphery.

    • Aggregate surface tension is inversely proportional to the amount of surface cadherins per cell; more cadherins lead to lower surface tension and internal sorting.

The Extracellular Matrix (ECM)

  • The Extracellular Matrix (ECM) is an insoluble, intricate network of macromolecules secreted by cells, forming the environment that surrounds them.

  • Cell-to-cell interactions are not isolated events; they occur in close coordination with, and are significantly influenced by, the surrounding ECM conditions.

  • Key ECM Proteins (Figure 4.9):

    • Proteoglycans

    • Fibronectin

    • Laminin

    • Collagen

  • Basal Lamina: A specialized layer of ECM secreted by epithelial cells, serving as the foundation upon which an epithelium sits.

  • Integrins (Figures 4.10, Page 14):

    • Cells adhere to ECM components using transmembrane adhesion molecules called integrins.

    • Integrins act as receptors for ECM molecules like fibronectin.

    • During Xenopus gastrulation, fibronectin plays a vital role in orienting the movements of mesodermal cells by providing attachment points for integrin-expressing cells.

    • The critical role of integrins in cell-matrix and cell-cell adhesion in physiology and disease was recognized with the 2022 Lasker Award.

Epithelial-Mesenchymal Transition (EMT)

  • EMT (Figure 4.11) is a significant developmental phenomenon.

  • It involves a series of events where epithelial cells lose their cell-cell adhesion, apical-basal polarity, and tight junctions, and acquire characteristics of mesenchymal cells (e.g., increased motility, altered ECM interactions).

  • This transition is crucial for many developmental processes, including gastrulation, neural crest migration, and organ development.

Modes of Intercellular Communication: Juxtacrine and Paracrine Signaling (Figure 4.1)

  • Juxtacrine Signaling (Figure 4.1A):

    • Involves direct contact between neighboring cells.

    • Signaling proteins from the inducing cell interact directly with receptor proteins on the adjacent responding cell.

    • Can occur via:

      • Homophilic binding: Identical surface proteins on two cells bind to each other.

      • Heterophilic binding: Different surface proteins on two cells bind to each other.

  • Paracrine Signaling (Figure 4.1B):

    • Involves signaling over a distance.

    • Signaling proteins (ligands) are secreted by one cell.

    • These ligands diffuse through the extracellular space and bind to receptors on neighboring cells, or even distant cells, to elicit a response.

    • Responses can be fast or slow depending on the specific ligand and receptor kinetics.

Induction and Competence: Driving Developmental Processes

  • Induction: The ability of one cell or tissue (the inducer) to direct the developmental trajectory of neighboring cells or tissues (the responder).

    • Many inductive interactions are mediated by secreted paracrine factors.

  • Competence: The intrinsic ability of a cell or tissue to respond to a specific inductive signal.

  • Reciprocal Induction: A scenario where an inducer simultaneously becomes the induced tissue in response to signals from the tissue it initially induced.

    • Example: In vertebrate eye development, the optic vesicle acts as an inducer for lens formation. Once the lens has formed, it, in turn, signal to the optic vesicle and surrounding ectoderm, inducing other ocular tissues.

  • Inductive Cascades: Organ formation is driven by a series of sequential inductive events, where one induction leads to another, creating a cascade of developmental signals.

Types of Inductive Interactions

  • Instructive Interaction:

    • A signal from the inductive cell is absolutely necessary to initiate a new pattern of gene expression in the responding cell.

    • The responding cell is not predetermined to develop in a specific way without this de novo signaling.

    • Example (Page 17): If a Xenopus optic vesicle is transplanted under a new region of head ectoderm, it will instruct that ectoderm to form a lens, a fate it would not normally undertake.

  • Permissive Interaction:

    • The responding tissue has already been genetically programmed or