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Cellular Mechanisms of Development Chapter 19. 2 Overview of Development Development is the successive process of systematic gene-directed changes throughout.

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Presentation on theme: "Cellular Mechanisms of Development Chapter 19. 2 Overview of Development Development is the successive process of systematic gene-directed changes throughout."— Presentation transcript:

1 Cellular Mechanisms of Development Chapter 19

2 2 Overview of Development Development is the successive process of systematic gene-directed changes throughout an organism’s life cycle -Can be divided into four subprocesses: -Growth (cell division) -Differentiation -Pattern formation -Morphogenesis

3 3 Cell Division After fertilization, the diploid zygote undergoes a period of rapid mitotic divisions -In animals, this period is called cleavage -Controlled by cyclins and cyclin- dependent kinases (Cdks) During cleavage, the zygote is divided into smaller & smaller cells called blastomeres -Moreover, the G1 and G2 phases are shortened or eliminated

4 4 Cell Division

5 5 Cyclin Degradation C M G2G2 interphase mitosis cytokinesis G2G2 S G1G1 M C Mitosis DNA Synthesis Adult Cell Cycle S G1G1 Cdk /G1 cyclin Cdk / S cyclin Mitosis DNA Synthesis Active Cell Cycle of Early Frog Blastomere Active Cyclin Synthesis Active Cdk /G2 cyclin C M S S M Cdk / cyclin Cdk Inactive a.b.

6 6 Cell Division Caenorhabditis elegans -One of the best developmental models -Adult worm consists of 959 somatic cells -Transparent, so cell division can be followed -Researchers have mapped out the lineage of all cells derived from the fertilized egg

7 7 Nematode Lineage Map a. b. Egg and sperm line Egg Pharynx Cuticle-making cellsVulva Egg Sperm Adult Nematode Vulva Gonad Nervous system Pharynx Intestine Cuticle Intestine Nervous system Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

8 8 Cell Division Blastomeres are nondifferentiated and can give rise to any tissue Stem cells are set aside and will continue to divide while remaining undifferentiated -Tissue-specific: can give rise to only one tissue -Pluripotent: can give rise to multiple different cell types -Totipotent: can give rise to any cell type

9 9 Cell Division Cleave in mammals continues for 5-6 days producing a ball of cells, the blastocyst -Consists of: -Outer layer = Forms the placenta -Inner cell mass = Forms the embryo -Source of embryonic stem cells (ES cells)

10 10 Egg SpermBlastocystEmbryo Embryonic stem-cell culture Inner cell mass Once sperm cell and egg cell have joined, cell cleavage produces a blastocyst. The inner cell mass of the blastocyst develops into the human embryo. Embryonic stem cells (ES cells) are isolated from the inner cell mass

11 11 Cell Division A plant develops by building its body outward -Creates new parts from stem cells contained in structures called meristems -Meristematic stem cells continually divide -Produce cells that can differentiate into the various plant tissues -Leaves, roots, branches, and flowers The plant cell cycle is also regulated by cyclins and cyclin-dependent kinases

12 12 Cell Differentiation A human body contains more than 210 major types of differentiated cells Cell determination commits a cell to a particular developmental pathway -Can only be “seen” by experiment -Cells are moved to a different location in the embryo -If they develop according to their new position, they are not determined

13 13 Donor No donor Recipient Before Overt Differentiation Recipient After Overt Differentiation NormalNot Determined (early development) Determined (later development) Tail cells are transplanted to head Tail cells develop into head cells in head Tail cells develop into tail cells in head Tail cells are transplanted to head TailHead Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

14 14 Cell Differentiation Cells initiate developmental changes by using transcriptional factors to change patterns of gene expression Cells become committed to follow a particular developmental pathway in one of two ways: 1) via differential inheritance of cytoplasmic determinants 2) via cell-cell interactions

15 15 Cell Differentiation Cytoplasmic determinants -Tunicates are marine invertebrates -Tadpoles have tails, which are lost during metamorphosis into the adult -Egg contains yellow pigment granules -Become asymmetrically localized following fertilization -Cells that inherit them form muscles

16 16 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. a. n 2n2n Embryo (diploid) 2n Larva (diploid) 2n Sperm (haploid) n Egg (haploid) n Pigment granules Adult tunicate (diploid) 2n MEIOSIS METAMORPHOSIS

17 17 Cell Differentiation Cytoplasmic determinants -Female parent provides egg with macho-1 mRNA -Encodes a transcription factor that can activate expression of muscle- specific genes

18 18 Cell Differentiation Induction is the change in the fate of a cell due to interaction with an adjacent cell If cells of a frog embryo are separated: -One pole (“animal pole”) forms ectoderm -Other pole (“vegetal pole”) forms endoderm -No mesoderm is formed If the two pole cells are placed side-by-side, some animal-pole cells form the mesoderm

19 19 Cell Differentiation Another example of induction is the formation of notochord and mesenchyme in tunicates -Arise from mesodermal cells that form at the vegetal margin of 32-cell stage embryo -Cells receive a chemical signal from underlying endodermal cells -Anterior cells differentiate into notochord -Posterior cells differentiate into mesenchyme

20 20 Anterior Posterior AnteriorPosterior a. b.c. 21 FGF signaling Sagittal section Longitudinal section Longitudinal section Dorsal nerve cord (NC) Mesenchymal cells (Mes) Tail muscle cells (Mus) 32-Cell Stage64-Cell Stage Anterior Posterior 2 1 Notochord (Not)Ventral endoderm (En) Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

21 21 Cell Differentiation The chemical signal is a fibroblast growth factor (FGF) molecule -The FGF receptor is a tyrosine kinase that activates a MAP kinase cascade -Produces a transcription factor that triggers differentiation Thus, the combination of macho-1 and FGF signaling leads to four different cell types

22 22 Cell Differentiation a. FGF Signal received? Mesenchyme Muscle Notochord FGF Signal received? Macho-1 inherited? Nerve cord First StepCell TypesSecond Step Yes No Yes No Yes No FGF FGF Receptor Ras/MAPK Pathway T-Ets Macho-1 Cell membrane P Mesenchyme Precursor Cells Suppression of muscle genes and activation of mesenchyme genes b.

23 23 Cell Differentiation No FGF FGF Receptor Ras/MAPK Pathway T-Ets Cell membrane Nerve cord Precursor Cells FGF FGF Receptor Transcription of notochord genes P Notochord Precursor Cells No FGF FGF Receptor Ras/MAPK Pathway Transcription of muscle genes Muscle Precursor Cells Suppression of notochord genes and activation of nerve cord genes No Macho-1 Macho-1 Cell membrane T-Ets Ras/MAPK Pathway

24 24 Cloning Until very recently, biologists thought that determination and cell differentiation were irreversible in animals Nuclear transplant experiments in mammals were attempted without success -Finally, in 1996 a breakthrough Geneticists at the Roslin Institute in Scotland performed the following procedure:

25 25 Cloning 1. Differentiated mammary cells were removed from the udder of a six-year old sheep 2. Eggs obtained from a ewe were enucleated 3. Cells were synchronized to a resting state 4. The mammary and egg cells were combined by somatic cell nuclear transfer (SCNT) 5. Successful embryos (29/277) were placed in surrogate mother sheep 6. On July 5, 1996, Dolly was born

26 26 DevelopmentImplantationBirth of CloneGrowth to Adulthood Embryo begins to develop in vitro. Embryo is implanted into surrogate mother. After a five-month pregnancy, a lamb genetically identical to the sheep from which the mammary cell was extracted is born. Embryo PreparationCell FusionCell Division Mammary cell is extracted and grown in nutrient- deficient solution that arrests the cell cycle. Egg cell is extracted. Nucleus is removed from egg cell with a micropipette. Nucleus containing source Mammary cell is inserted inside covering of egg cell. Electric shock fuses cell membranes and triggers cell division.

27 27 Cloning Dolly proved that determination in animals is reversible -Nucleus of a differentiated cell can be reprogrammed to be totipotent Reproductive cloning refers to the use of SCNT to create an animal that is genetically identical to another -Scientists have cloned cats, rabbits, rats, mice, goats and pigs

28 28 Cloning Reproductive cloning has inherent problems 1. Low success rate 2. Age-associated diseases Normal mammalian development requires precise genomic imprinting -The differential expression of genes based on parental origin Cloning fails because there is not enough time to reprogram the genome properly

29 29 Cloning In therapeutic cloning, stem cells are cloned from a person’s own tissues and so the body readily accepts them Initial stages are the same as those of reproductive cloning -Embryo is broken apart and its embryonic stem cells extracted -Grown in culture and then used to replace diseased or injured tissue

30 30 Cloning The skin cell nucleus is inserted into the enucleated human egg cell. Cell cleavage occurs as the embryo begins to develop in vitro. The embryo reaches the blastocyst stage The nucleus from a skin cell of a diabetic patient is removed. The nucleus from a skin cell of a healthy patient is removed. Early embryoBlastocyst Inner cell mass ES cells Diabetic patient Healthy patient

31 31 Cloning Therapeutic Cloning Reproductive Cloning Embryonic stem cells (ES cells) are extracted and grown in culture. The blastocyst is kept intact and is implanted into the uterus of a surrogate mother. The resulting baby is a clone of the healthy patient. The stem cells are developed into healthy pancreatic islet cells needed by the patient. The healthy tissue is injected or transplanted into the diabetic patient. Healthy pancreatic islet cells Diabetic patient

32 32 Cloning Human embryonic stem cells have enormous promise for treating a wide range of diseases -However, stem cell research has raised profound ethical issues Very few countries have permissive policy towards human reproductive cloning -However, many permit embryonic stem cell research

33 33 Cloning Early reports on a variety of adult stem cells indicated that they may be pluripotent -Since then these results have been challenged

34 34 Pattern Formation In the early stages of pattern formation, two perpendicular axes are established -Anterior/posterior (A/P, head-to-tail) axis -Dorsal/ventral (D/V, back-to-front) axis Polarity refers to the acquisition of axial differences in developing structures Position information leads to changes in gene activity, and thus cells adopt a fate appropriate for their location

35 35 Drosophila Embryogenesis Drosophila produces two body forms -Larva – Tubular eating machine -Adult – Flying sex machine axes are established Metamorphosis is the passage from one body form to another Embryogenesis is the formation of a larva from a fertilized egg

36 36 Drosophila Embryogenesis Before fertilization, specialized nurse cells move maternal mRNAs into maturing oocyte -These mRNA will initiate a cascade of gene activations following fertilization Embryonic nuclei do not begin to function until approximately 10 nuclear divisions later

37 37 Drosophila Embryogenesis After fertilization, 12 rounds of nuclear division without cytokinesis produces a syncytial blastoderm -4000 nuclei in a single cytoplasm Membranes grow between the nuclei forming the cellular blastoderm Within a day of fertilization, a segmented, tubular body is formed

38 38 c. b. Nurse cells AnteriorPosterior Movement of maternal mRNA Oocyte Follicle cells Fertilized egg a. d. e. Three larval stages Syncytial blastoderm Cellular blastoderm Nuclei line up along surface, and membranes grow between them to form a cellular blastoderm. Segmented embryo prior to hatching Metamorphosis Abdomen Thorax Head Hatching larva Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Nucleus Embryo

39 39 Drosophila Embryogenesis Nüsslein-Volhard and Wieschaus elucidated how the segmentation pattern is formed -Earned the 1995 Nobel Prize Two different genetic pathways control the establishment of the A/P and D/V polarity -Both involve gradients of morphogens -Soluble signal molecules that can specify different cell fates along an axis

40 40 About 21/2 hours after fertilization, bicoid protein turns on a series of brief signals from so- called gap genes. The gap proteins act to divide the embryo into large blocks. In this photo, fluorescent dyes in antibodies that bind to the gap proteins Krüppel (orange) and Hunchback (green) make the blocks visible; the region of overlap is yellow. Forming the SegmentsLaying Down the Fundamental Regions Setting the Stage for Segmentation Bicoid Hairy KrüppelHunchback Engrailed Establishing the Polarity of the Embryo Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Fertilization of the egg triggers the production of bicoid protein from maternal RNA in the egg. The bicoid protein diffuses through the egg, forming a gradient. This gradient determines the polarity of the embryo, with the head and thorax developing in the zone of high concentration (green fluorescent dye in antibodies that bind bicoid protein allows visualization of the gradient). About 0.5 hr later, the gap genes switch on the “pair-rule” genes, which are each expressed in seven stripes. This is shown for the pair- rule gene hairy. Some pair-rule genes are only required for even- numbered segments while others are only required for odd numbered segments. The final stage of segmentation occurs when a “segment- polarity” gene called engrailed divides each of the seven regions into halves, producing 14 narrow compartments. Each compartment corresponds to one segment of the future body. There are three head segments (H, bottom right), three thoracic segments (T, upper right), and eight abdominal segments (A, from top right to bottom left).

41 41 Establishment of the A/P axis Nurse cells secrete maternally produced bicoid and nanos mRNAs into the oocyte -Differentially transported by microtubules to opposite poles of the oocyte -bicoid mRNA to the future anterior pole -nanos mRNA to the future posterior pole -After fertilization, translation will create opposing gradients of Bicoid and Nanos proteins

42 42 a. b. bicoid mRNA moves toward anterior end bicoid mRNA Movement of maternal mRNA Nucleus Microtubules Nurse cells Follicle cells nanos mRNA moves toward posterior end PosteriorAnterior PosteriorAnterior nanos mRNA Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

43 43 Establishment of the A/P axis Bicoid and Nanos control translation of two other maternal mRNAs, hunchback and caudal, that encode transcription factors -Hunchback activates anterior structures -Caudal activates posterior structures The two mRNAs are not evenly distributed -Bicoid inhibits caudal mRNA translation -Nanos inhibits hunchback mRNA translation

44 44 Concentration Anterior a. Oocyte mRNAs c. Early cleavage embryo proteins b. After fertilization Posterior nanos mRNA hunchback mRNA bicoid mRNA caudal mRNA Nanos protein Hunchback protein Bicoid protein Caudal protein Concentration AnteriorPosterior nanos mRNA hunchback mRNA bicoid mRNA caudal mRNA Nanos protein Hunchback protein Bicoid protein Caudal protein Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

45 45 Establishment of the D/V axis Maternally produced dorsal mRNA is placed into the oocyte -Not asymmetrically localized Oocyte nucleus synthesizes gurken mRNA -Accumulates in a crescent on the future dorsal side of embryo After fertilization, a series of steps results in selected transport of Dorsal into ventral nuclei, thus forming a D/V gradient

46 46

47 47 Production of Body Plan The body plan is produced by sequential activation of three classes of segmentation genes 1. Gap genes -Map out the coarsest subdivision along the A/P axis -All 9 genes encode transcription factors that activate the next gene class

48 48 Production of Body Plan 2. Pair-rule genes -Divide the embryo into seven zones -The 8 or more genes encode transcription factors that regulate each other, and activate the next gene class 3. Segment polarity genes -Finish defining the embryonic segments

49 49 Production of Body Plan Segment identity arises from the action of homeotic genes -Mutations in them lead to the appearance of normal body parts in unusual places -Ultrabithorax mutants produce an extra pair of wings

50 50 Production of Body Plan Homeotic gene complexes -The HOM complex genes of Drosophila are grouped into two clusters -Antennapedia complex, which governs the anterior end of the fly -Bithorax complex, which governs the posterior end of the fly -Interestingly, the order of genes mirrors the order of the body parts they control

51 51 Production of Body Plan Homeotic gene complexes -All of these genes contain a conserved 180-base sequence, the homeobox -Encodes a 60-amino acid DNA-binding domain, the homeodomain -Homeobox-containing genes are termed Hox genes -Vertebrates have 4 Hox gene clusters

52 52 Production of Body Plan Drosophila HOM genes Thorax Antennapedia complex HeadAbdomen Bithorax complex Fruit fly embryo Mouse Hox 1 Hox 2 Hox 3 Hox 4 Mouse embryo a.b. Drosophila HOM ChromosomesMouse Hox Chromosomes labpbDfdScrAntpUbxabd-Aabd-B

53 53 Pattern Formation in Plants The predominant homeotic gene family in plants is the MADS-box genes -Found in most eukaryotic organisms, although in much higher numbers in plants MADS-box genes encode transcriptional regulators, which control various processes: -Transition from vegetative to reproductive growth, root development and floral organ identity

54 54 Morphogenesis Morphogenesis is the formation of ordered form and structure -Animals achieve it through changes in: -Cell division -Cell shape and size -Cell death -Cell migration -Plants use these except for cell migration

55 55 Morphogenesis Cell division -The orientation of the mitotic spindle determines the plane of cell division in eukaryotic cells -If spindle is centrally located, two equal-sized daughter cells will result -If spindle is off to one side, two unequal daughter cells will result

56 56 Morphogenesis Cell shape and size -In animals, cell differentiation is accomplished by profound changes in cell size and shape -Nerve cells develop long processes called axons -Skeletal muscles cells are large and multinucleated

57 57 Morphogenesis Cell death -Necrosis is accidental cell death -Apoptosis is programmed cell death -Is required for normal development in all animals -“Death program” pathway consists of: -Activator, inhibitor and apoptotic protease

58 58 a.b. InhibitorCED-9Bcl-2 CED-4Apaf1 Caspase-8 or -9 Apoptosis CED-3 Apoptosis Inhibitor: Activator: Apoptotic Protease: Caenorhabditis elegansMammalian CellOrganism Inhibition Activation Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

59 59 Morphogenesis Cell migration -Cell movement involves both adhesion and loss of adhesion between cells and substrate -Cell-to-cell interactions are often mediated through cadherins -Cell-to-substrate interactions often involve complexes between integrins and the extracellular matrix (ECM)

60 60 Development of Seed Plants Plant development occurs in five main stages: 1. Early embryonic cell division -First division is off-center -Smaller cell divides to form the embryo -Larger cell divides to form suspensor -Cells near it ultimately form the root -Cells on the other end, form the shoot

61 61 Development of Seed Plants 2. Embryonic tissue formation -Three basic tissues differentiate: -Epidermal, ground and vascular 3. Seed formation -1-2 cotyledons form -Development is arrested 4. Seed germination -Development resumes -Roots extend down, and shoots up

62 62 Development of Seed Plants 5. Meristematic development and morphogenesis -Apical meristems at the root and shoot tips generate a large numbers of cells -Form leaves, flowers and all other components of the mature plant

63 63 a. Early cell division Embryo Suspensor b. Tissue formation d. Germination c. Seed formation meristem Seed wall Shoot apical meristem Root apical Shoot apical meristem Cotyledons e. Meristematic development and morphogenesis Root apical meristem Epidermal cells Ground tissue cells Vascular tissue cells Cotyledons Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

64 64 Environmental Effects Both plant and animal development are affected by environmental factors -Germination of a dormant seed proceeds only under favorable soil and day conditions -Reptiles have a temperature-dependent sex determination (TSD) mechanism -The water flea Daphnia changes its shape after encountering a predatory fly larva

65 65 Environmental Effects

66 66 Environmental Effects In mammals, embryonic and fetal development have a longer time course -Thus they are more subject to the effects of environmental contaminants, and blood- borne agents in the mother -Thalidomide, a sedative drug -Many pregnant women who took it had children with limb defects

67 67 Environmental Effects Endocrine disrupting chemicals (EDCs) -Interfere with synthesis, transport or receptor-binding of endogenous hormones -Derived from three main sources -Industrial wastes (polychlorinated biphenyls or PCBs) -Agricultural practices (DDT) -Effluent of sewage-treatment plants

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