Mechanisms of Human Health and Disease. Developmental Biology

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Mechanisms of Human Health and Developmental Biology Joe Schultz joe.

org D6 1 Dev Bio: Mysteries How do fertilized eggs become adults?

1 Mechanisms of Human Health and Developmental Biology Joe Schultz D6 1 Dev Bio: Mysteries How do fertilized eggs become adults? How do adults make more adults? Why and how do nearly all mammals have similar body plans? How are arms made? When is an embryo considered living? 2 Hospital - COPYING PROHIBITED 1

Limb Development 3 Dev Bio: Gametogenesis

2 Dev Bio: Overview 1. Gametogenesis 2. Fertilization 3. Cleavage 4. Gastrulation 5. Body Axis formation 6. Germ Layers 7. Neurlization 8. Homeobox Genes 9. Limb Development 3 Dev Bio: Gametogenesis Gametogenesis: The formation of new sex cells Hospital - COPYING PROHIBITED 2

3 Dev Bio: Fertilization Fertilization: Union of sex cells Dev Bio: Gastrulation Gastrulation: Morphology of the embryo is drastically altered by cell migration. Hospital - COPYING PROHIBITED 3

Dev Bio: Gastrulation Animation Gastrulation: The most important event in your life. http://courses.biology.utah.

jpg Play animation: gastrulation-keller.mov http://courses.biology.utah.

html Dev Bio: Body Axis Formation Animal/Vegetal: Maternally determined Radial to bilaterial symmetry transition:

4 Dev Bio: Gastrulation Animation Gastrulation: The most important event in your life. Play animation: gastrulation-keller.mov /Images_movies/gastrulation.html Dev Bio: Body Axis Formation Animal/Vegetal: Maternally determined Radial to bilaterial symmetry transition: Point of fertilization and first cleavage Dorsol/Ventral: Rotation of fertilization, induction of Speman Organizer Anterior/Posterior: Established during D/V and posterior is formation of doral lip of blastopore Hospital - COPYING PROHIBITED 4

5 Dev Bio: Germ Layer Dev Bio: Germ Layer Mechanisms of Formation Hospital - COPYING PROHIBITED 5

6 Dev Bio: Neuralization Dev Bio: Organogenesis Hospital - COPYING PROHIBITED 6

structures. http://hoopermuseum.earthsci.

7 Dev Bio: Body Plan Homology Hox Genes A common genetic ancestor explains homologous structures. Dev Bio: Body Plan Hospital - COPYING PROHIBITED 7

8 Dev Bio: Limb Development Dev Bio: Limb Development Hospital - COPYING PROHIBITED 8

9 Dev Bio: Limb Development Dev Bio: The Visible Embryo Homework Hospital - COPYING PROHIBITED 9

10 Mechanisms of Human Health and Cell Signaling Joe Schultz D5 19 Cell Signaling : Mysteries How does an organ know when to stop growing? What is a cellular signal? How do cells get signals to change? What is the mechanism to trigger change? How are waterfalls similar to cell signaling events? What can cause cells to keep dividing beyond control? Hospital - COPYING PROHIBITED 10

Cell Signaling : Table of Contents Regulation of Cellular Growth Cell Signaling Growth Factors Receptors EGF Case Study Signaling Mechanisms/ Cascades 21 Cell Signaling : Regulation of Cellular

11 Cell Signaling : Table of Contents Regulation of Cellular Growth Cell Signaling Growth Factors Receptors EGF Case Study Signaling Mechanisms/ Cascades 21 Cell Signaling : Regulation of Cellular Growth Size of an organism/tissue is tightly controlled by regulation of cell proliferation, growth, and death. Regulatory signals control growth autonomously (autocrine), locally (paracrine signaling) and at a distance (endocrine) Cell replication is regulated by complex pathways activated by cell surface or intracellular receptors, to which growth factors bind, and a cascade of intracellular proteins regulate the cell cycle machinery. 22 Hospital - COPYING PROHIBITED 11

12 Cell Signaling : Regulators of Cell Replication Growth factor dependence Anchorage dependence Contact inhibition Senescence Apoptosis Nutrient and oxygen supply 23 Cell Signaling : Components: Signaling molecules Signal + Receiver = Ligand + Receptor Peptides / Proteins - Growth Factors Amino acid derivatives - epinephrine, histamine Other small biomolecules - ATP Steroids, prostaglandins Gases - Nitric Oxide (NO) Photons Damaged DNA Odorants, tastants 24 Hospital - COPYING PROHIBITED 12

Cell Signaling : Components: Signaling Molecules: Growth Factors Factor Primary Activity Comments PDGF EGF TGF-α FGF NGF Principal Source platelets, endothelial cells, placenta submaxillary gland,

mesenchymal, glial and epithelial cells may be important for normal wound healing promotes proliferation of many cells; inhibits some stem cells; induces mesoderm to form in early embryos promotes

anti-inflammatory (suppresses cytokine production and class II MHC expression), promotes wound healing, inhibits macrophage and lymphocyte proliferation IGF-I primarily liver promotes proliferation

13 Cell Signaling : Components: Signaling Molecules: Growth Factors Factor Primary Activity Comments PDGF EGF TGF-α FGF NGF Principal Source platelets, endothelial cells, placenta submaxillary gland, Brunners gland common in transformed cells wide range of cells; protein is associated with the ECM promotes proliferation of connective tissue, glial and smooth muscle cells promotes proliferation of mesenchymal, glial and epithelial cells may be important for normal wound healing promotes proliferation of many cells; inhibits some stem cells; induces mesoderm to form in early embryos promotes neurite outgrowth and neural cell survival Erythropoietin kidney promotes proliferation and differentiation of erythrocytes TGF-β activated TH 1 cells (T-helper) and natural killer (NK) cells anti-inflammatory (suppresses cytokine production and class II MHC expression), promotes wound healing, inhibits macrophage and lymphocyte proliferation IGF-I primarily liver promotes proliferation of many cell types IGF-II variety of cells promotes proliferation of many cell types primarily of fetal origin two different protein chains form 3 distinct dimer forms; AA, AB and BB related to EGF at least 19 family members, 4 distinct receptors several related proteins first identified as proto-oncogenes; trka (tracka), trkb, trkc at least 100 different family members related to IGF-II and proinsulin, also called Somatomedin C related to IGF-I and proinsulin Cell Signaling : Components: Signaling Molecules: Growth Factors PDGF TGF FGF Hospital - COPYING PROHIBITED 13

Cell Signaling : Components: Cellular Receptors: G-protein Cellular Receptors: Proteins located within the plasma membrane that have an extracellular (outside) ligand binding domain and in

G protein-coupled receptors (GPCRs), also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors (GPLR), comprise a

14 Cell Signaling : Components: Cellular Receptors: G-protein Cellular Receptors: Proteins located within the plasma membrane that have an extracellular (outside) ligand binding domain and in intracellular (internal) signalling domain. G protein-coupled receptors (GPCRs), also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors (GPLR), comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses. G protein-coupled receptors are found only in eukaryotes, including yeast, plants, choanoflagellates,[1] and animals. The ligands that bind and activate these receptors include lightsensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins. G protein-coupled receptors are involved in many diseases, and are also the target of around half of all modern medicinal drugs Cell Signaling : Components: Cellular Receptors Side View Top View EXTRAcellular INTRAcellular Structural alpha helices Hospital - COPYING PROHIBITED 14

15 Cell Signaling : Components: Growth Factor Cellular Receptors Cell Signaling : Components: Growth Factor Receptor Tyrosine Kinases Hospital - COPYING PROHIBITED 15

Cell Signaling : Kinase Kinase: An enzyme that transfers high energy phosphate groups to target molecules ATP: Molecular Money Sigma Aldrich catalogue

16 Cell Signaling : Kinase Kinase: An enzyme that transfers high energy phosphate groups to target molecules ATP: Molecular Money Sigma Aldrich catalogue Cell Cycle: Inside the Cell: Energetics 32 Hospital - COPYING PROHIBITED 16

Cell Cycle: Phosphorylation Serine Threonine Tyrosine R-group similiarity?? mechanism for kinase activity? http://www.3dchem.com/molecules.asp?

receptor, NEU/HER2, HER3 insulin receptor, IGF-1 receptor PDGF receptors, c-kit FGF receptors vascular endothelial cell growth factor (VEGF) receptor hepatocyte growth factor (HGF) and scatter factor

17 Cell Cycle: Phosphorylation Serine Threonine Tyrosine R-group similiarity?? mechanism for kinase activity? 33 Cell Signaling : Components: Growth Factor Receptor Tyrosine Kinases Characteristics of the Common Classes of RTKs Class Examples Structural Features of Class I II III IV V VI VII EGF receptor, NEU/HER2, HER3 insulin receptor, IGF-1 receptor PDGF receptors, c-kit FGF receptors vascular endothelial cell growth factor (VEGF) receptor hepatocyte growth factor (HGF) and scatter factor (SC) receptors neurotrophin receptor family (trka, trkb, trkc) and NGF receptor cysteine-rich sequences cysteine-rich sequences; characterized by disulfide-linked heterotetramers contain 5 immunoglobulin-like domains; contain the kinase insert contain 3 immunoglobulin-like domains as well as the kinase insert; acidic domain contain 7 immunoglobulin-like domains as well as the kinase insert domain heterodimeric like the class II receptors except that one of the two protein subunits is completely extracellular. The HGF receptor is a proto-oncogene that was originally identified as the Met oncogene contain no or few cysteine-rich domains; NGFR has leucine rich domain Hospital - COPYING PROHIBITED 17

GFSO : Components: GF RTK Activation RS/TK (to the right) RTK (below) Cell Signaling : EGF Case Study Epidermal Growth Factor Epidermal growth factor or EGF is a growth factor that plays an important

[1] EGF acts by binding with high affinity to epidermal growth factor receptor (EGFR) on the cell surface and stimulating the intrinsic protein-tyrosine kinase activity of the receptor.

18 GFSO : Components: GF RTK Activation RS/TK (to the right) RTK (below) Cell Signaling : EGF Case Study Epidermal Growth Factor Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation and differentiation. Human EGF is a 6045 Da protein with 53 amino acid residues and three intramolecular disulfide bonds.[1] EGF acts by binding with high affinity to epidermal growth factor receptor (EGFR) on the cell surface and stimulating the intrinsic protein-tyrosine kinase activity of the receptor. The tyrosine kinase activity in turn initiates a signal transduction cascade which results in a variety of biochemical changes within the cell - a rise in intracellular calcium levels, increased glycolysis and protein synthesis, and increases in the expression of certain genes including the gene for EGFR - that ultimately lead to DNA synthesis and cell proliferation Hospital - COPYING PROHIBITED 18

Cell Signaling : EGF Players Draw arrows to each Growth Factors Small proteins Growth Factor Receptors Proteins on the surface of the cells Intracellular Signaling Transducers Nuclear Transcription

19 Cell Signaling : EGF Players Draw arrows to each Growth Factors Small proteins Growth Factor Receptors Proteins on the surface of the cells Intracellular Signaling Transducers Nuclear Transcription Factors Cell Signaling : Signaling Mechanisms: Step by step 1. Binding of growth factor to extracellular receptor 2. Receptor dimerization (draw) 3. Cross autophosphorylation Hospital - COPYING PROHIBITED 19

com/uk/orc/bin/9780199264728/image/c04f05.

20 Cell Signaling : Signaling Mechanisms: Step by step continued 4. Intracellular receptor activation 5. Phosphorylation exchanges 6. Activation of intracellular transducers 7. Cascades of kinases 8. Regulation of gene expression Cell Signaling : Structural Considerations: Binding Closer look at how a receptor binds its signaling molecule Conformational changes structure yields function. Hospital - COPYING PROHIBITED 20

21 Cell Signaling : Cascade Examples: RTK Signal Transduction Summary Cell Signaling : Cascade Examples Hospital - COPYING PROHIBITED 21

22 Cell Signaling : Cascade Examples: MAPK and TCF-B Pathway Cell Signaling : Cascade Examples: RTK ST-PI3K Pathway P Hospital - COPYING PROHIBITED 22

Cell-Cell Communication in Development

Biology 4361 - Developmental Biology Cell-Cell Communication in Development October 2, 2007 Cell-Cell Communication - Topics Induction and competence Paracrine factors inducer molecules Signal transduction