Transcript Lecture 3
Introduction to Developmental Biology Mathematical Biology Lecture 3 James A. Glazier (All Uncredited Figures From Wolpert et al. Principles of Development) Development in Ninety Minutes What is Development? Biological Process by Which a Fertilized Egg Organism http://www.stanford.edu/group/Urchin/LP/ [Lauren Palumbi] http://www.kvarkadabra.net/images/articles/Regeneracijaorganov_1_original.jpg Physical Process Which Translates Genetic Information (Genotype) Structure and Behavior (Phenotype) http://nomadlife.org/dna.jpg http://www.bib.sdu.dk/sund/grafik/vesalius.jpg Development as Self-Organization • Interesting to Physicists and Mathematicians because largely self-organized not prespecified. • About 5×104 genes and 109 cells. Genome does not contain enough information to specify each cell. • Even if it did, development would be fragile if completely specified. • Instead, highly robust at all levels. Main Processes • • • • Cell Differentiation Cell Movement Cell Proliferation and Death Cellular Secretion and Absorption of Extracellular Scaffolding Differentiation • • • One Cell Type Initially, Many in Adult All Cells Have the Same Genes (modulo immune cells…) Cell Type Determined by Epigenetic Effects: – Pattern of Gene Expression – Internal Structure – Metabolic Factors Gene Switching • Promoters Turn On Repressors Turn Off Translation of Genes into Messenger RNA (mRNA) • Can Also Regulate the Lifetime of mRNA and the Translation of mRNA into Proteins • More Exotic Regulation as Well • Regulation has Complex Feedback and Interactions in the Gene Regulatory Network • Enzymes can Methylate Stretches of DNA Turning Genes off “Permanently” • Hence Differentiation is Usually a One-Way process: Less DifferentiatedMore Differentiated • Opposite Ends of Spectrum: Stem Cells, Terminally Differentiated Cells (e.g. Neurons) Homeotic Regulatory Genes Cell Lines Fundamental Distinction: Germ Cells (immortal) vs. Somatic Cells (disposable) Germ Layers: Mesoderm—Muscle, Cartilage, Bone, Germ Cells, Internal Organs (Heart, Blood, Kidneys, ….) Endoderm—Gut, Lungs, Liver Ectoderm—Skin, Nervous System How Does a Cell Know What to Differentiate Into? •Cell Does Not Carry a Road Map! Only Knows its Own Composition and Local Environment. •Positional Information: •Part of the Cytoplasm in the Egg from Which Cell Derived. •Contact With Other Cells or Substrate. •Reception of Extracellular Diffusants. •Previous Differentiation History of Cell. Reaction Diffusion Equation (Turing) after Cook & Murray Two diffusing Species:Activator A; Inhibitor B A f ( A, B) d A 2 A t B g ( A, B) d B 2 B t f g where 0, 0,0 d A d B A B Activator-Inhibitor Interactions in Cartilage Pattern Formation Philip Maini Consequences of Differentiation • Cells— • • • • • • Change Shape Polarize (Become Asymmetric) Move Divide/Die Send and Respond to Chemical and Electrical Signals Secrete and Absorb Extracellular Material Cell Shape Changes • Determined by Cytoskeleton – Microfilaments (Actin)—Cell Movement, Force Generation, Cell Division. – Microtubules (Tubulin)—Compressive Strength, Cell Shape and Polarization, Chromosome Separation, Long-range Transport inside Cell. – Intermediate Filaments—Tensile Strength – Molecular Motors—Myosin, Kinesin, Dynein,… Cell Polarization • Localization of Receptors and Junctions on Surface of Cell. • Asymmetry of Cytoskeleton. • E.g. of Egg (Animal and Vegetal Poles), Neuron (Axon, Dendrite and Soma). • Most Cells form Monolayer Sheets (Epithelia). • Epithelial Cells have Different Properties on their Apical, Basal and Lateral Surfaces. They Bind Tightly to their Neighbors and Variably on their Tops and Bottoms. • Mesenchymal Cells are More Symmetrical and Form Connective Tissue. Cell Movement Cells Move Long Distances During Development. Move by Protruding and Retracting Filopodia or Lamellipodia (Leading Edge) Shape Changes During Movement May be Random or Directed. Move By Sticking Selectively to Other Cells (Differential Adhesion) Move By Sticking to Extracellular Material (Haptotaxis) Move By Following External Chemical Gradients (Chemotaxis) Can also have Bulk Movement: Secretion of ECM Differential Cell Division Oriented Cell Division Chemotaxis: Play Movies Mechanical Changes in Organogenesis Feedback Loops • Not Simply: SignalDifferentiationPattern (Known as Prepatterning). • Cells Create Their Own Environment, by Moving and Secreting New Signals, so Signaling Feeds Back on Itself. • Hence Self-Organization and Robustness. Development of Body Plan • Specification of Body Axes • Cleavage • Gastrulation (Formation of Primitive Streak— Anterior-Posterior) • Somitogenesis (Formation of AP compartments) • Organogenesis Initial Axis Determination Cleavage Basics • Period of rapid cell division (up to once every ten minutes). • No cell growth (no interphase). • Karyokinesis (Chromosome replication) and Cytokinesis (Cell division) may occur separately. • Cytokinesis may be missing or partial. • Karyokinesis and Cytokinesis are usually synchronous throughout the embryo. • Little or no relative cell movement. • Many types in different species. Types of Cleavage • Holoblastic (entire egg cleaves): usually little yolk in egg. – Isolecithal (symmetric yolk) • • • • Radial—Echinoderms Spiral—Molluscs Bilateral—Ascidians/Tunicates (sea squirts, jellyfish) Rotational—Mammals – Mesolecithal (yolk mostly at one end) • Radial—Amphibians • Bilateral—Cephalopods • Meroblastic (partial cleavage): lots of yolk – Telolecithal (yolk at one end) • Bilateral Discoidal—Reptiles, Fish, Birds – Centrolecithal (yolk in middle) • Superficial—Arthropods Query: How can closely related families differ so radically at the very earliest stages of development? How could they have changed their developmental programs in a non-lethal way? Gastrulation (Formation of Germ Layers) Neurulation/Somitogenesis Organogenesis/Limb Development Dictyostelium discoideum Plant Development Lung Development Kidney Development Other Possibilities • • • • • Vascular Development Bone Development Tumor Growth Ear (Otic) Development Liver (Hepatic) Development