🐣Developmental Biology Unit 7 – Cell Migration and Morphogenesis

Key Concepts in Cell Migration and Morphogenesis

• Cell migration plays a crucial role in various developmental processes (gastrulation, neural crest migration, wound healing)
• Morphogenesis the process by which tissues and organs develop their shape and structure through coordinated cell movements and rearrangements
• Cell migration can be individual (mesenchymal) or collective (epithelial sheets)
  • Individual migration cells move independently of each other
  • Collective migration cells maintain cell-cell contacts and move as a cohesive group
• Cell polarity establishment of asymmetry within a cell, essential for directed migration
• Cytoskeletal dynamics the reorganization of actin and microtubule networks drives cell shape changes and movement
• Cell adhesion molecules (cadherins, integrins) mediate cell-cell and cell-matrix interactions during migration
• Chemotaxis the directed movement of cells in response to chemical gradients (growth factors, chemokines)
• Mechanotransduction the ability of cells to sense and respond to mechanical cues from their environment

Cellular Mechanisms Driving Movement

• Actin polymerization drives the formation of protrusions (lamellipodia, filopodia) at the leading edge of migrating cells
• Myosin II-mediated contraction generates force for cell body translocation and rear retraction
• Focal adhesions dynamic structures that link the cytoskeleton to the extracellular matrix, providing traction for movement
• Membrane trafficking (endocytosis, exocytosis) regulates the recycling of adhesion molecules and membrane dynamics during migration
• Rho GTPases (Rho, Rac, Cdc42) key regulators of cytoskeletal dynamics and cell polarity
  • Rho promotes stress fiber formation and cell contractility
  • Rac stimulates lamellipodia formation and membrane ruffling
  • Cdc42 induces filopodia formation and establishes cell polarity
• Microtubules provide structural support and facilitate intracellular transport during migration
• Intermediate filaments contribute to cell mechanical stability and resistance to stress

Molecular Players and Signaling Pathways

• Growth factors (EGF, FGF, VEGF) stimulate cell migration through receptor tyrosine kinase (RTK) signaling
• Chemokines (CXCL12, CCL21) guide cell migration during development and immune responses
• Integrins transmembrane receptors that mediate cell-matrix adhesion and activate intracellular signaling cascades
• Cadherins calcium-dependent cell-cell adhesion molecules that maintain tissue integrity during collective migration
• Wnt signaling pathway regulates cell polarity, migration, and morphogenetic movements (convergent extension)
• TGF-β signaling pathway induces epithelial-mesenchymal transition (EMT) and promotes cell migration during development and cancer progression
• Notch signaling pathway controls cell fate decisions and influences cell migration in various contexts (angiogenesis, neural crest migration)
• Hippo signaling pathway regulates cell proliferation, survival, and migration through the transcriptional co-activators YAP/TAZ

Extracellular Matrix Interactions

• Extracellular matrix (ECM) provides structural support and signaling cues for migrating cells
• ECM composition (collagen, fibronectin, laminin) varies across tissues and developmental stages
• Integrins mediate cell-ECM adhesion and transduce mechanical and chemical signals
  • Integrin activation leads to the formation of focal adhesions and activation of downstream signaling pathways (FAK, Src)
• Matrix metalloproteinases (MMPs) degrade ECM components, facilitating cell invasion and remodeling
• Heparan sulfate proteoglycans (HSPGs) bind growth factors and regulate their availability and signaling
• Hyaluronan a glycosaminoglycan that influences cell migration and tissue hydration
• Durotaxis the directed movement of cells towards regions of higher substrate stiffness
• Contact guidance the alignment and migration of cells along ECM fibers or topographical features

Developmental Contexts and Examples

• Gastrulation the formation of the three germ layers (ectoderm, mesoderm, endoderm) through coordinated cell movements (invagination, involution, epiboly)
• Neural crest migration a highly migratory population of cells that give rise to various cell types (neurons, glia, melanocytes, craniofacial structures)
• Angiogenesis the formation of new blood vessels from pre-existing ones, involves endothelial cell migration and tube formation
• Wound healing the coordinated migration of keratinocytes, fibroblasts, and immune cells to close a wound and restore tissue integrity
• Drosophila border cell migration a model system for studying collective cell migration during oogenesis
• Zebrafish lateral line development involves the collective migration of a group of cells called the primordium
• Xenopus convergent extension the narrowing and lengthening of the body axis during gastrulation, driven by polarized cell intercalation
• Chick primitive streak formation the site of gastrulation in avian embryos, where epiblast cells undergo EMT and migrate to form the mesoderm and endoderm

Techniques for Studying Cell Migration

• Live cell imaging allows the visualization of cell migration in real-time using fluorescent reporters and microscopy techniques (confocal, light sheet)
• Cell tracking software enables the quantification of cell migration speed, directionality, and trajectory
• In vitro assays (wound healing, transwell, microfluidic devices) provide controlled environments to study cell migration under specific conditions
• In vivo lineage tracing using genetic labeling techniques (Cre-loxP, fluorescent proteins) to follow the fate and migration of specific cell populations
• Optogenetics the use of light-sensitive proteins to control cell behavior and signaling pathways with spatial and temporal precision
• Biomaterial scaffolds engineered matrices that mimic the physical and biochemical properties of the ECM to study cell migration in 3D environments
• Traction force microscopy a technique that measures the forces exerted by migrating cells on their substrate
• Atomic force microscopy (AFM) a high-resolution imaging technique that can also measure the mechanical properties of cells and tissues

Morphogenesis and Tissue Formation

• Convergent extension a conserved morphogenetic process that elongates tissues through polarized cell intercalation
• Branching morphogenesis the formation of branched structures (lungs, mammary glands, kidneys) through coordinated cell migration and proliferation
• Epithelial folding the bending and invagination of epithelial sheets to create complex 3D structures (neural tube, optic cup)
• Cell sorting the segregation of different cell types based on their differential adhesion properties
• Planar cell polarity (PCP) the coordinated orientation of cells within the plane of an epithelium, essential for directed cell migration and tissue organization
• Mechanically-driven morphogenesis the shaping of tissues through the generation and transmission of mechanical forces (tension, compression)
• Tissue fusion the merging of two separate tissue layers or structures to form a continuous unit (palate, heart)
• Organoids self-organizing 3D cell cultures that recapitulate the structure and function of mini-organs, useful for studying morphogenesis and disease modeling

Clinical Implications and Future Directions

• Cancer metastasis the spread of cancer cells from the primary tumor to distant sites, involves cell migration and invasion
  • Targeting cell migration pathways (Rho GTPases, FAK, MMPs) is a promising strategy for anti-metastatic therapies
• Wound healing disorders (chronic wounds, fibrosis) result from impaired cell migration and tissue repair
• Regenerative medicine harnessing the migratory and morphogenetic potential of stem cells to regenerate damaged or lost tissues
• Organ-on-a-chip microfluidic devices that mimic the structure and function of human organs, enabling the study of cell migration and drug screening
• Single-cell sequencing technologies provide high-resolution insights into the molecular heterogeneity of migrating cell populations
• Computational modeling integration of experimental data with mathematical models to predict and simulate cell migration and morphogenesis
• Biomaterials and tissue engineering designing synthetic matrices and scaffolds that guide cell migration and tissue formation for regenerative applications
• Gene editing (CRISPR-Cas9) a powerful tool for dissecting the genetic basis of cell migration and morphogenesis, and for developing targeted therapies