Cell-Cell Communication and Morphogenesis

Cell-Cell Communication: Morphogenesis

Learning Objectives

  • Explain cell-cell and cell-extracellular matrix (ECM) interactions.

  • Describe cell communication via juxtacrine and paracrine signaling.

  • Understand how one cell or tissue induces the development of neighboring cells or tissues.

  • Identify key components of major developmental signaling pathways: Fibroblast Growth Factor (FGF), Hedgehog/Sonic Hedgehog (Shh), Wnt, Transforming Growth Factor-beta (TGF-$\beta$), and Notch-Delta.

  • Explain what a morphogen is and how morphogen gradients are formed.

  • Describe the mechanism of lateral inhibition in development.

Key Terms

  • Morphogenesis

  • Cadherin

  • Extracellular matrix (ECM)

  • Integrin

  • Epithelial-mesenchymal transition (EMT)

  • Induction

  • Morphogen

  • Gradient

  • Threshold

  • Juxtacrine signaling

  • Paracrine signaling

  • FGF

  • Hedgehog (Hh)

  • Sonic Hedgehog (Shh)

  • Wnt

  • TGF-$\beta$

  • Notch

  • Delta

  • Heparan sulfate proteoglycan (HSPG)

  • Cytoneme

  • Lateral inhibition

Morphogenesis: The Construction of Organized Form

  • Morphogenesis is the construction of organized form.

  • Development involves more than just cell differentiation.

  • Cells must be ordered and organized to create different shapes and establish specific connections within tissues and organs.

Cell-to-Cell Communication

  • There are two primary modes of cell-to-cell communication:

    • (A) Juxtacrine signaling: Involves direct contact between cells.

      • Homophilic binding: Occurs when identical proteins on two different cells bind to each other.

      • Heterophilic binding: Occurs when different proteins on two different cells bind to each other.

    • (B) Paracrine signaling: Involves the secretion of signaling proteins (ligands) by one cell, which then diffuse to act on neighboring cells over a short distance.

      • These signaling proteins bind to specific receptors on the target cells.

Adhesion and Sorting: The Physics of Morphogenesis

  • Question: How are separate tissues formed from populations of cells (e.g., how do bone cells stick to other bone cells rather than mixing with muscle cells)?

  • Differential Cell Affinity: Pioneering experiments by Townes and Holtfreter (1955) on amphibian neurulae cells demonstrated that disaggregated cells reaggregate and sort out according to their cell type, forming distinct regions (e.g., epidermis, neural plate, mesoderm, endoderm).

    • Each cell type sorts out into its own region, indicating a differential affinity between cell types.

  • Thermodynamics Model of Cell Interactions – Differential Adhesion Hypothesis: This model explains cell sorting based on differences in cell surface tensions.

    • Cells with greater surface tension or weaker adhesion tend to sort to the periphery, while cells with lower surface tension or stronger adhesion tend to sort to the center.

    • This creates a hierarchy of cell sorting mediated by decreasing surface tensions.

  • Cadherins: Major Cell Adhesion Molecules

    • Cadherins are calcium-dependent adhesion molecules crucial for cell-cell adhesion.

    • They are anchored inside the cell by a complex of proteins called catenins, linking them to the cytoskeleton.

    • Different cadherins mediate adhesion in specific tissues:

      • E-cadherin: Epithelial cells

      • P-cadherin: Placenta

      • N-cadherin: Neural cells

      • R-cadherin: Retina

      • Protocadherins: A diverse group of cadherin-related proteins.

    • Importance of Cadherin Amount: The relative amount of cadherin expression on cell surfaces dictates cell sorting and aggregate surface tension.

      • Cells with more N-cadherin often sort to the center.

      • Differences in P-cadherin vs. E-cadherin expression also lead to specific sorting patterns (e.g., P-cadherin > E-cadherin, P-cadherin == E-cadherin, P-cadherin < E-cadherin result in different sorting outcomes).

The Extracellular Matrix (ECM) as a Source of Developmental Signals

  • Cell-cell interactions occur within and are often influenced by their environment.

  • The extracellular matrix (ECM) is an insoluble network of macromolecules secreted by cells, forming their immediate environment.

  • Key ECM Proteins:

    • Proteoglycans: Highly glycosylated proteins that form a hydrated gel-like substance.

    • Fibronectin: Plays crucial roles in cell adhesion, migration, and differentiation.

    • Laminin: A major component of the basal lamina.

    • Collagen: Provides structural integrity to tissues.

  • Basal Lamina: A specialized layer of ECM secreted by epithelial cells, providing a foundation for the epithelium.

  • Integrins: Receptors for ECM Molecules

    • Integrins are transmembrane receptors that mediate cell adhesion to the ECM.

    • For example, fibronectin helps orient the movements of mesodermal cells during Xenopus gastrulation, and integrins are their receptors.

    • The 2022 Lasker Award recognized discoveries concerning integrins as key mediators of cell-matrix and cell-cell adhesion in physiology and disease.

Epithelial-Mesenchymal Transition (EMT)

  • EMT is a fundamental developmental phenomenon.

  • It involves a series of events where epithelial cells (which are typically polarized and form sheets) lose their cell-cell adhesion and acquire migratory, invasive mesenchymal characteristics.

  • This process is crucial for various developmental events, including gastrulation and neural crest migration.

Induction and Competence

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

    • In many cases, induction is mediated by paracrine factors.

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

  • Reciprocal Induction: Inductive interactions are often reciprocal, meaning an inducer can become the induced, and vice-versa.

    • Example: The optic vesicle induces lens formation. Once the lens forms, it then induces other tissues, including the optic vesicle itself.

  • Cascades of Inductive Events: Organ formation typically relies on intricate cascades of inductive events, where each induction triggers the next step in development.

  • Two Major Modes of Inductive Interaction:

    • Instructive Interaction: A signal from the inducing cell is absolutely necessary for initiating new gene expression in the responding cell.

      • Example: A Xenopus optic vesicle induces a new lens when transplanted under a new region of head ectoderm, demonstrating that the signal instructs the ectoderm to form a lens.

    • Permissive Interaction: The responding tissue has already been specified (its developmental fate determined) and only requires an appropriate environment that allows the expression of these predetermined traits.

      • Example: Decellularized ECM (lacking cells but retaining the structural scaffold) can allow cardiomyocytes to recreate contracting heart muscle, providing the permissive environment for their inherent developmental program to proceed.

Morphogen Gradients and Signal Transduction Cascades

  • Discovery of Soluble Inducers vs. Physical Contact: Grobstein (1956) observed that some inductive events occurred through a filter separating tissues, while others were blocked, indicating that some inducers are soluble molecules (paracrine factors) and others require physical cell-cell contact.

  • Morphogen: A diffusible biochemical molecule that can determine the fate of a cell based on its concentration.

    • The term