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Developmental Biology
AP Bio 18:4 21:6 47:2 (part), 3 Wild-type mouse embryo 9.5 days post coitum
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Our focus: Timing and Coordination Gene Expression Interactions, Cell Signaling
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In particular, you should be familiar with
Differential gene expression Cytoplasmic determinants Induction and signaling Tissue-specific proteins Pattern formation, homeotic genes and protein gradients Early embryo developmental stages Apoptosis Cancer and development of cells
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Insights into development have been obtained froms studying
Slime Molds Nematode worm C. elegans Fruit Flies Zebrafish Frog Embryos Chick Embryos Mice
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(a) Fertilized eggs of a frog (b) Newly hatched tadpole
Fig Figure From fertilized egg to animal: What a difference four days makes (a) Fertilized eggs of a frog (b) Newly hatched tadpole
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Zebrafish are often used for embryological research.
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Their embryos are transparent.
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Gene expression orchestrates the developmental programs of animals
A program of differential gene expression leads to the different cell types in a multicellular organism During embryonic development, a fertilized egg gives rise to many different cell types Cell types are organized successively into tissues, organs, organ systems, and the whole organism Gene expression orchestrates the developmental programs of animals
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A Genetic Program for Embryonic Development
The transformation from zygote to adult results from cell division, cell differentiation, and morphogenesis
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Cell differentiation is the process by which cells become specialized in structure and function
The physical processes that give an organism its shape constitute morphogenesis Differential gene expression results from genes being regulated differently in each cell type Materials in the egg can set up gene regulation that is carried out as cells divide
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Source of developmental information: Cytoplasmic Determinants and Inductive Signals
An egg’s cytoplasm contains RNA, proteins, and other substances that are distributed unevenly in the unfertilized egg Cytoplasmic determinants are maternal substances in the egg that influence early development As the zygote divides by mitosis, cells contain different cytoplasmic determinants, which lead to different gene expression
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(a) Cytoplasmic determinants in the egg
Fig a Unfertilized egg cell Sperm Nucleus Fertilization Two different cytoplasmic determinants Zygote Mitotic cell division Figure Sources of developmental information for the early embryo Two-celled embryo (a) Cytoplasmic determinants in the egg
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The other important source of developmental information is the environment around the cell, especially signals from nearby embryonic cells In the process called induction, signal molecules from embryonic cells cause transcriptional changes in nearby target cells Thus, interactions between cells induce differentiation of specialized cell types
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Work with the nematode C
Work with the nematode C. elegans has shown that induction requires the transcriptional regulation of genes in a particular sequence.
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(b) Induction by nearby cells
Fig b NUCLEUS Early embryo (32 cells) Signal transduction pathway Signal receptor Figure Sources of developmental information for the early embryo Signal molecule (inducer) (b) Induction by nearby cells
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Spemann Experiment Spemann carried out an experiment to test whether substances were located asymmetrically in the gray crescent. Gray crescent not bisected equally
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The gray crescent acts as an “organizer” by inducing cells to become certain parts of the embryo.
Embryo blastomeres that did not receive part of the gray crescent area did not develop normally. A signaling protein perhaps?
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Sequential Regulation of Gene Expression During Cellular Differentiation
Determination commits a cell to its final fate: it is the progressive restriction of developmental potential as the embryo develops Determination precedes differentiation Cell differentiation is marked by the expression of tissue-specific proteins
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For example Myoblasts produce muscle-specific proteins and form skeletal muscle cells (myo – muscle) MyoD is one of several “master regulatory genes” that produce proteins that commit the cell to becoming skeletal muscle The MyoD protein is a transcription factor that binds to enhancers of various target genes
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Master regulatory gene myoD Other muscle-specific genes
Fig Nucleus Master regulatory gene myoD Other muscle-specific genes DNA Embryonic precursor cell OFF OFF Figure Determination and differentiation of muscle cells
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MyoD protein (transcription Myoblast factor) (determined) Nucleus
Fig Nucleus Master regulatory gene myoD Other muscle-specific genes DNA Embryonic precursor cell OFF OFF mRNA OFF MyoD protein (transcription factor) Myoblast (determined) Figure Determination and differentiation of muscle cells
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(fully differentiated cell)
Fig Nucleus Master regulatory gene myoD Other muscle-specific genes DNA Embryonic precursor cell OFF OFF mRNA OFF MyoD protein (transcription factor) Myoblast (determined) Figure Determination and differentiation of muscle cells mRNA mRNA mRNA mRNA Myosin, other muscle proteins, and cell cycle– blocking proteins MyoD Another transcription factor Part of a muscle fiber (fully differentiated cell)
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Why doesn’t myoD change any type of embryonic cell?
Probably a combination of regulatory genes are necessary for differentiation is required.
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Pattern Formation: Setting Up the Body Plan
Pattern formation is the development of a spatial organization of tissues and organs In animals, pattern formation begins with the establishment of the major axes Positional information, the molecular cues (cytoplasmic determinants and inductive signals) control pattern formation, and tell a cell its location relative to the body axes and to neighboring cells
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Pattern formation has been extensively studied in the fruit fly Drosophila melanogaster
Combining anatomical, genetic, and biochemical approaches, researchers have discovered developmental principles common to many other species, including humans
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The Life Cycle of Drosophila
In Drosophila, cytoplasmic determinants in the unfertilized egg determine the axes before fertilization After fertilization, the embryo develops into a segmented larva with three larval stages
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Head Thorax Abdomen 0.5 mm Dorsal Right BODY AXES Anterior Posterior
Fig a Head Thorax Abdomen 0.5 mm Dorsal Right BODY AXES Anterior Posterior Figure Key developmental events in the life cycle of Drosophila Left Ventral (a) Adult
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(b) Development from egg to larva
Fig b Follicle cell 1 Egg cell developing within ovarian follicle Nucleus Egg cell Nurse cell 2 Unfertilized egg Egg shell Depleted nurse cells Fertilization Laying of egg 3 Fertilized egg Embryonic development Figure Key developmental events in the life cycle of Drosophila 4 Segmented embryo 0.1 mm Body segments Hatching 5 Larval stage (b) Development from egg to larva
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Genetic Analysis of Early Development: Scientific Inquiry
Edward B. Lewis, Christiane Nüsslein-Volhard, and Eric Wieschaus won a Nobel 1995 Prize for decoding pattern formation in Drosophila Homeotic genes control pattern formation in the late embryo, larva, and adult.
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A mutation in regulatory genes, called homeotic genes, caused this.
Fig Eye Leg Antenna Figure Abnormal pattern formation in Drosophila Wild type Mutant antennapedia gene
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Ultrabithorax (Ubx) gene mutation in Drosophila
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Homeotic Genes One example are the Hox and ParaHox genes which are important for segmentation, another example is the MADS-box-containing genes in the ABC model of flower development. Chap 21:6
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The Homeobox Homeotic genes contain a 180 nucleotide sequence called a homeobox found in regulatory genes . This homeobox has been found in inverts and verts as well as plants.
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The homeobox DNA sequence evolved very early in the history of life and has been conserved virtually unchanged for millions of years. Differences arise due to different gene expressions.
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ABC model of flower development
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Molecular basis of differentiation:
The A, B, and C genes are transcription factors. Different transcription factors are needed together to turn on a developmental gene program--such as A and B needed to initiate the program for petals. What turns on the different transcription factors in different cells? Induction and inhibition by one cell signaling to a neighboring cell.
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Fate Mapping Fate maps are general territorial diagrams of embryonic development Classic studies using frogs indicated that cell lineage in germ layers is traceable to blastula cells *Chap 47 (3)
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Blastomeres injected with dye
Fig Epidermis Epidermis Central nervous system 64-cell embryos Notochord Blastomeres injected with dye Mesoderm Endoderm Blastula Neural tube stage (transverse section) Larvae Figure Fate mapping for two chordates (a) Fate map of a frog embryo (b) Cell lineage analysis in a tunicate
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Central nervous system Epidermis
Fig a Epidermis Central nervous system Epidermis Notochord Mesoderm Endoderm Figure 47.21a Fate mapping for two chordates Blastula Neural tube stage (transverse section) (a) Fate map of a frog embryo
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Axis Establishment Maternal effect genes encode for cytoplasmic determinants that initially establish the axes of the body of Drosophila These maternal effect genes are also called egg-polarity genes because they control orientation of the egg and consequently the fly
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Bicoid: A Morphogen Determining Head Structures
One maternal effect gene, the bicoid gene, affects the front half of the body An embryo whose mother has a mutant bicoid gene lacks the front half of its body and has duplicate posterior structures at both ends
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EXPERIMENT Tail Head Wild-type larva Tail Tail Mutant larva (bicoid)
Fig a EXPERIMENT Tail Head A8 T1 T2 T3 A7 A1 A6 A2 A3 A4 A5 Wild-type larva Tail Tail Figure Is Bicoid a morphogen that determines the anterior end of a fruit fly? A8 A8 A7 A7 A6 Mutant larva (bicoid)
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RESULTS Anterior end Bicoid mRNA in mature unfertilized egg
Fig b RESULTS Fertilization, translation of bicoid mRNA 100 µm Anterior end Figure Is Bicoid a morphogen that determines the anterior end of a fruit fly? Bicoid mRNA in mature unfertilized egg Bicoid protein in early embryo
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CONCLUSION Nurse cells Egg bicoid mRNA Developing egg
Fig c CONCLUSION Nurse cells Egg bicoid mRNA Developing egg Figure Is Bicoid a morphogen that determines the anterior end of a fruit fly? Bicoid mRNA in mature unfertilized egg Bicoid protein in early embryo
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Bicoid mRNA, Bicoid Protein (red)
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This phenotype suggests that the product of the mother’s bicoid gene is concentrated at the future anterior end This hypothesis is an example of the gradient hypothesis, in which gradients (amounts) of substances called morphogens establish an embryo’s axes and other features
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The bicoid research is important for three reasons:
– It identified a specific protein required for some early steps in pattern formation – It increased understanding of the mother’s role in embryo development – It demonstrated a key developmental principle that a gradient of molecules can determine polarity and position in the embryo
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Cancer results from genetic changes that affect cell cycle control
The gene regulation systems that go wrong during cancer are the very same systems involved in embryonic development
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Types of Genes Associated with Cancer
Cancer can be caused by mutations to genes that regulate cell growth and division Tumor viruses can cause cancer in animals including humans Oncogenes are cancer-causing genes Proto-oncogenes are the corresponding normal cellular genes that are responsible for normal cell growth and division Conversion of a proto-oncogene to an oncogene can lead to abnormal stimulation of the cell cycle
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within a control element within the gene
Fig Proto-oncogene DNA Translocation or transposition: Gene amplification: Point mutation: within a control element within the gene New promoter Oncogene Oncogene Figure Genetic changes that can turn proto-oncogenes into oncogenes Normal growth- stimulating protein in excess Normal growth-stimulating protein in excess Normal growth- stimulating protein in excess Hyperactive or degradation- resistant protein
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Proto-oncogenes can be converted to oncogenes by
Movement of DNA within the genome: if it ends up near an active promoter, transcription may increase Amplification of a proto-oncogene: increases the number of copies of the gene Point mutations in the proto-oncogene or its control elements: causes an increase in gene expression
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Tumor-Suppressor Genes
Tumor-suppressor genes help prevent uncontrolled cell growth Mutations that decrease protein products of tumor-suppressor genes may contribute to cancer onset Tumor-suppressor proteins Repair damaged DNA Control cell adhesion Inhibit the cell cycle in the cell-signaling pathway
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Interference with Normal Cell-Signaling Pathways
Mutations in the ras proto-oncogene and p53 tumor-suppressor gene are common in human cancers Mutations in the ras gene can lead to production of a hyperactive Ras protein and increased cell division
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(a) Cell cycle–stimulating pathway
Fig a 1 Growth factor 1 MUTATION Hyperactive Ras protein (product of oncogene) issues signals on its own Ras 3 G protein GTP Ras GTP 2 Receptor 4 Protein kinases (phosphorylation cascade) NUCLEUS 5 Transcription factor (activator) DNA Figure Signaling pathways that regulate cell division Gene expression Protein that stimulates the cell cycle (a) Cell cycle–stimulating pathway
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(b) Cell cycle–inhibiting pathway
Fig b 2 Protein kinases MUTATION Defective or missing transcription factor, such as p53, cannot activate 3 Active form of p53 UV light 1 DNA damage in genome DNA Figure Signaling pathways that regulate cell division Protein that inhibits the cell cycle (b) Cell cycle–inhibiting pathway
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(c) Effects of mutations
Fig c EFFECTS OF MUTATIONS Protein overexpressed Protein absent Cell cycle overstimulated Increased cell division Cell cycle not inhibited Figure Signaling pathways that regulate cell division (c) Effects of mutations
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Suppression of the cell cycle can be important in the case of damage to a cell’s DNA; p53 prevents a cell from passing on mutations due to DNA damage Mutations in the p53 gene prevent suppression of the cell cycle
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The Multistep Model of Cancer Development
Multiple mutations are generally needed for full-fledged cancer; thus the incidence increases with age At the DNA level, a cancerous cell is usually characterized by at least one active oncogene and the mutation of several tumor-suppressor genes
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Hedgehog Signaling Pathway
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The Hedgehog Pathway is very important in development but after adult state is reached it is used in maintenance of stem cells.
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Development in Animals Chap 47 (part of 2, 3)
Timing and coordination to produce stages After fertilization, embryonic development proceeds through cleavage, gastrulation, and organogenesis The sperm’s contact with the egg’s surface initiates metabolic reactions in the egg that trigger the onset of embryonic development
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Important events regulating development occur during fertilization and the three stages that build the animal’s body: Cleavage: cell division creates a hollow ball of cells called a blastula Gastrulation: cells are rearranged into a three-layered gastrula Organogenesis: the three layers interact and move to give rise to organs
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(a) Fertilized egg (b) Four-cell stage (c) Early blastula
Fig. 47-6 (a) Fertilized egg Figure 47.6 Cleavage in an echinoderm embryo (b) Four-cell stage (c) Early blastula (d) Later blastula
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Gastrulation Gastrulation rearranges the cells of a blastula into a three-layered embryo, called a gastrula, which has a primitive gut The three layers produced by gastrulation are called embryonic germ layers The ectoderm forms the outer layer The endoderm lines the digestive tract The mesoderm partly fills the space between the endoderm and ectoderm
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These germ layers become:
Ectoderm – skin and nervous system Mesoderm – skeleton, muscles, circulatory, lining of body cavity Endoderm – lining of digestive and respiratory tract, liver, many glands (pancreas, thymus, thyroid, parathyroid)
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Reproductive system (except germ cells)
Fig ECTODERM MESODERM ENDODERM Epidermis of skin and its derivatives (including sweat glands, hair follicles) Epithelial lining of mouth and anus Cornea and lens of eye Nervous system Sensory receptors in epidermis Adrenal medulla Tooth enamel Epithelium of pineal and pituitary glands Notochord Skeletal system Muscular system Muscular layer of stomach and intestine Excretory system Circulatory and lymphatic systems Reproductive system (except germ cells) Dermis of skin Lining of body cavity Adrenal cortex Epithelial lining of digestive tract Epithelial lining of respiratory system Lining of urethra, urinary bladder, and reproductive system Liver Pancreas Thymus Thyroid and parathyroid glands
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http://www.gastrulation.org/Movie9_3.mov Fig. 47-9-6
Key Future ectoderm Future mesoderm Future endoderm Archenteron Blastocoel Filopodia pulling archenteron tip Animal pole Blastocoel Archenteron Blastocoel Blastopore Mesenchyme cells Ectoderm Vegetal plate Vegetal pole Mouth Figure 47.9 Gastrulation in a sea urchin embryo Mesenchyme cells Mesenchyme (mesoderm forms future skeleton) Digestive tube (endoderm) Blastopore 50 µm Anus (from blastopore)
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Gastrulation in the frog
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Early in vertebrate organogenesis, the notochord forms from mesoderm, and the neural plate (which will becomes the nervous system) forms from ectoderm
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Figure 47.12 Early organogenesis in a frog embryo
Neural folds Eye Somites Tail bud Neural fold Neural plate SEM 1 mm 1 mm Neural tube Neural crest cells Neural fold Neural plate Notochord Neural crest cells Coelom Somite Notochord Ectoderm Figure Early organogenesis in a frog embryo Archenteron (digestive cavity) Mesoderm Outer layer of ectoderm Endoderm Neural crest cells (c) Somites Archenteron (a) Neural plate formation Neural tube (b) Neural tube formation
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Central nervous system Epidermis
Fig a Epidermis Central nervous system Epidermis Notochord Mesoderm Endoderm Blastula Neural tube stage (transverse section) (a) Fate map of a frog embryo
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In humans, At completion of cleavage, the blastocyst forms
A group of cells called the inner cell mass develops into the embryo The trophoblast, the outer epithelium of the blastocyst, initiates implantation in the uterus. As implantation is completed, gastrulation begins
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will become embryo Endometrial epithelium (uterine lining) Uterus
Fig Endometrial epithelium (uterine lining) Uterus Inner cell mass Trophoblast Figure Four stages in early embryonic development of a human Blastocoel will become embryo
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Restriction of the Developmental Potential of Cells
In many species that have cytoplasmic determinants, only the very early stages of the embryo are totipotent. That is, only the zygote can develop into all the cell types in the adult As embryonic development proceeds, potency of cells becomes more limited
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Stem Cells of Animals A stem cell is a relatively unspecialized cell that can reproduce itself indefinitely and differentiate into specialized cells of one or more types Stem cells isolated from early embryos at the blastocyst stage are called embryonic stem cells; these are able to differentiate into all cell types The adult body also has stem cells, which replace nonreproducing specialized cells
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Importance of Apoptosis in development
Elimination of transitory organs and tissues. Examples include tadpole tails and gills. Tissue remodeling. Vertebrate limb bud development, removal of interdigital skin. Nutrients are reused!
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When the grim and reaper genes work together, they help guide cells in flies through their death process, apoptosis—much like that spectre of 15th century folklore, the Grim Reaper.
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Comparing plant and animal development
Since plants have rigid cell walls, there is no morphogenetic movement of cells. plant development depends upon differential rates of cell division then directed enlargement of cells.
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All postembryonic growth occur at meristems which give rise to all adult structures (shoots, roots, stems, leaves and flowers) and have the capacity to divide repeatedly and give rise to a number of tissues (like stem cells). Two meristems are established in the embryo, one at the root tip and one at the tip of the shoot. The developmental patterning of organs therefore continues throughout the life of the plant.
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Their fate is determined largely by their position but they do have signaling.
Homeotic genes control organ identity (ABC model) but genes are called Mad-box genes instead of Hox genes
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Similarities in development of plants and animals
Both involve a cascade of transcription factors But differences in regulatory genes as stated in previous slide
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Evo-Devo Comparing developmental processes of different multicellular organisms
Many groups of animals and plants, even distantly related ones, share similar molecular mechanisms for morphogenesis and pattern formation. These mechanisms can be thought of as “genetic toolkits”.
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Development produces morphology and much of morphological evolution occurs by modifications of existing development genes and pathways rather than the introduction of radically new developmental mechanisms.
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Our common ancestor
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