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Chapter 57: Cellular Mechanisms of Development

Chapter Outline

Chapter 57: Cellular Mechanisms of Development

 

57.0 Introduction
  1. All Cells in a Multicellular Organism Descend From a Single Cell

    1. Particular Lines of Cells Proceed Along Different Developmental Paths

    2. The Developmental Program Unfolds With Precision fig 57.1

57.1 Development is a regulated process

  1. Studying Development in Animals

    1. Multicellular Cell Specialization Controlled by Gene Expression

      1. Different cells express different genes at different times

      2. Cells determine which genes to activate when

      3. Animal development is rigidly controlled with less influence by environment fig 57.2

        1. Study animal with complexly arranged body – a mammal

        2. Study a less complex animal with intricate development – an insect

        3. Study a simple animal – a nematode

  2. Vertebrate Development

    1. Dynamic Series of Stages of Cell Movement and Organs Formation fig 57.3

    1. Cleavage

      1. Zygote is the initial vertebrate being

      2. One cell divides rapidly forming blastomeres, and solid ball of cells fig 57.4

      3. Embryo stays same size, cell number increases, cell size decreases

        1. Cells at animal pole form external body tissues

        2. Cells at vegetal pole from internal tissues

      4. Initial dorsal-ventral orientation associated with position of sperm entry

        1. Sperm entry corresponds to future belly

      5. After 12 divisions cleavage slows, gene transcription begins

    2. Formation of the blastula

      1. Outer blastomeres connected by tight junctions fig 57.5a

        1. Junctions are belts of protein encircling cell, welding it to neighbor

        2. Cell mass effectively separated from environment

      2. At sixteen-cell stage cells at interior pump Na+ from interior to intercellular spaces

        1. Forms osmotic gradient in intercellular spaces

        2. Water moves from cells to enlarging intercellular spaces

        3. Spaces combine to form a cavity in cell mass

      3. Resulting hollow ball of cells is the blastula fig 57.5b

    3. Gastrulation

      1. Gastrula forms when wall of blastula at vegetal pole pushes inward fig 57.5c

        1. Cell extensions called lamellipodia help in cell movement

        2. Resembles collapsed tennis ball, process called gastrulation

        3. Embryo becomes bilaterally symmetrical

        4. Has central gut tube that opens to outside

      2. Embryo develops three germ layers

        1. Endoderm forms tube of primitive gut, most internal organs

        2. Outer cells are ectoderm form skin and nervous system

        3. Mesoderm forms notochord, bones, blood vessels, connective tissue, muscles

    4. Neurulation

      1. Presence of notochord triggers thickening of an ectodermal zone fig 57.5d

      2. Cells elongate, form wedge shape and roll into a tube

      3. Neural tube formed through this process of neurulation

    5. Cell migration

      1. Variety of cells migrate to form distant tissues fig 57.5e

        1. Follow specific path to particular location

        2. Neural crest pinches off from neural tube forms sense organs

        3. Somites migrate from central blocks of muscle forming skeletal muscles

      2. Receptor proteins of migrating cells interact with destination tissues to cease movement

    6. Organogenesis and growth

      1. Basic vertebrate plan established when body is only a few millimeters long

      2. Tissues develop into organs fig 57.5f

      3. Size increases enormously, number of cells increases by a million times fig 57.5g

  3. Insect Development

    1. Insect Development Quite Different from that of Mammals

    1. Many insects possess two distinctly different body forms

      1. Tubular eating machine called a larva

      2. Second form has wings and legs

      3. Change in body form called metamorphosis

      4. Exemplified by the fruit fly, Drosophila fig 57.6

    2. Maternal genes

      1. Construction of egg begins development before fertilization

      2. Nurse cells move their mRNA into end of egg nearest them fig 57.7a

      3. Maternal gene mRNAs positioned in specific locations in egg

      4. After divisions daughter cells contain different maternal products

      5. Action of maternal, not zygotic, genes controls initial development

    3. Syncytial blastoderm

      1. Nuclear divisions without cytokinesis produce syncytial blastoderm fig 57.7b

        1. Twelve round of division produce 400 nuclei within a single cytoplasm

        2. Nuclei in different sections communicate freely, but experience different maternal products

      2. Nuclei spread apart and grow intervening membranes form hollow ball of cells

      3. Followed by embryo folding and development of primary tissues

      4. Development similar to that of vertebrates

      5. Tubular body form called a larva

    4. Larval instars

      1. As larva feeds it grows, sheds its outer chitinous skin

      2. Body size expands before exoskeleton hardens

      3. Drosophila produce three larval instar stages in four days fig 57.7c

    5. Imaginal disks

      1. A dozen groups of cells are set aside in the abdomen of the larva fig 57.7d

      2. Called imaginal disks

      3. Have no role in the larva, form key parts of adult body

    6. Metamorphosis

      1. Hard shell forms around larva, now called pupa fig 57.7e

      2. Cells break down, release nutrients then used by imaginal disks

      3. Disks associate with each other to assemble adult fly

      4. Metamorphosis of larva to pupa to adult takes four days

      5. Adult emerges from split pupal shell

57.2 Multicellular organisms employ the same basic mechanisms of development

  1. Multicellular Organisms Develop According to Molecular Mechanisms

    1. Mechanisms Similar Among Most Multicellular Animals

      1. Mechanisms evolved early in the history of life

      2. Six mechanisms are of particular importance

  2. Cell Movement

    1. Cells Migrate During Many Developmental Stages

      1. May travel great distances before reaching ultimate destination

      2. Tissues contain cells from very different parts of early embryo

      3. Cells move via cell adhesion molecules like cadherins

        1. Span plasma membrane, protrude into cytoplasm, extend from cell surface

        2. Cytoplasmic portion attached to cytoskeleton actin or intermediate filaments

        3. Extracellular portion has five 100 amino acid segments with Ca++ sites

        4. Ca++ binding sites attach cadherin to other cells fig 57.9

        5. Cadherin links to another of same type, joining cytoskeletons of two cells

          1. Dozens of different kinds of cadherins discovered

          2. Helps sort cells with different cadherins into separate masses

          3. Cause for assembly of different imaginal disks

        6. Calcium-independent cell adhesion molecules assist cadherins

          1. Include neural cell adhesion molecules (N-CAMs)

          2. Expressed by migrating nerve cells

    2. Much Tissue Volume Is Space Between Cells

      1. Spaces filled with network of molecules secreted by surrounding cells

        1. Include matrix of protein linked polysaccharides, proteoglycans

        2. Contain embedded fibrous proteins like collagen, elastin, fibronectin

      2. Migrating cells traverse intercellular matrix via integrins fig 57.10

        1. Integrins attach to cytoskeleton actin filaments, protrude like two hands

        2. Protruding integrins attach to(hands grasp) fibrous portion of matrix

        3. Provides anchor and initiate cellular changes

          1. Alter growth of cytoskeleton

          2. Change way in which cell secretes materials into matrix

      3. Migration changes patterns of cell adhesion

        1. Migrating cell extends projections that probe environment

        2. Cell tugged different directions by different temporary attachments

        3. Literally feels its way to ultimate target site

  3. Induction

    1. Mosaic versus Regulative Development

      1. Initial cells created by cleavage contain different developmental signals

        1. Signals called determinants, pattern called mosaic development

        2. Individual cells set off on different developmental paths

        3. Occurs in Drosophila

      2. Blastomeres in mammals receive equal sets of determinants

        1. Body form determined by cell-cell interactions

        2. Called regulative development

      3. Few cases of strict mosaic development, cell-cell interactions play important role

      4. Demonstration of the importance of cell-cell interactions

        1. Separate cells of early blastula and allow to develop

          1. Ones from animal pole develop characteristics of ectoderm

          2. Ones from vegetal pole develop characteristics of endoderm

          3. Neither develop characteristics of mesoderm

          4. Mesoderm develops from animal pole cells growing next to vegetal pole cells

        2. Induction: Switching cell from one path of development to another fig 57.11

        3. Inducing cells secrete proteins that serve as intercellular signals

          1. Signals produce abrupt changes in patterns of gene transcription

    2. Role of Organizers in Development

      1. Organizers produce signal molecules that convey positional information

        1. Have profound effect influence on development of surrounding cells

        2. Act as signal beacons, inform surrounding cells of their distance from organizer

        3. If close, concentration of signal molecule is greater

        4. Signal molecules called morphogens fig 57.12

        5. Few morphogens identified, vital for determining relative developmental position

      2. Same morphogen can have different effect at different concentrations fig 57.13

        1. Dependent on distance from organizer

        2. In Xenopus low level of activin morphogen causes cells to become epidermis

        3. Slightly higher levels make cells into muscles

        4. Still higher level causes cells to become notochord

  4. Determination

    1. Developing Cells May Exhibit Totipotency

      1. Mammalian egg symmetrical in contents and shape

        1. As in all cells of mammalian egg equal up to eight-cell stage

        2. Cells are totipotent, capable of expressing all genes of genome

        3. If cells separated, can all develop into normal individual

        4. Used to produce identical offspring in valuable cattle

      2. Can do reverse, combine cells of eight cell stage into one individual

        1. Called a chimera fig 57.14

        2. Contains cells from different genetic lines

      3. After eight-cell stage mammalian cells become different

        1. Due to cell-cell interactions

        2. Future developmental fate of cells becomes irreversible

        3. Determination is a commitment to a particular developmental path

          1. Move cell in brain of early gastrula amphibian embryo, cell undetermined

          2. Cell will develop same way as new neighbors

          3. Transplant cell from late gastrula stage, cell determined

          4. Cell develops into neural tissue regardless of new location

      4. Determination versus differentiation

        1. Differentiation is cell specialization produced at end of developmental path

        2. Cell can be determined but not yet differentiated

        3. Example: Cells of Drosophila eye imaginal disk

          1. Cells fully determined to produce an eye

          2. Cells undifferentiated through most of development

    2. Molecular Mechanism of Determination

      1. Gene regulatory proteins initiate development changes

        1. When genes are activated they further reinforce their own activation

        2. Developmental switch is deterministic, initiates particular chain of events

        3. Cells may not undergo differentiation till later time

          1. Requires interaction of other factors with regulatory protein

          2. Cause protein to activate additional genes

        4. When switch is thrown cell is fully committed to certain developmental path

      2. Partial commitment to development associated with positional labels

        1. Reflect cell's location in embryo

        2. Influence how pattern of body develops

        3. Example: Chick embryo cell transplantation

        1. Leg bud cell (to become thigh) transplanted to wing bud (produces wing tip)

        2. Cell becomes toe rather than thigh or wing tip

        3. Cell committed to be leg, but not committed to be particular part of leg

    3. Is Determination Irreversible?

      1. Once thought to be irreversible

        1. Research in 1950-60 provided supporting information

        2. Removed nucleus from frog egg, replaced it with nucleus from body cell

        3. Transplanted nucleus from advanced embryo developed into tadpole and died

      2. Nuclear transplant experiments unsuccessful till 1984, sheep cloned

        1. Used cell from embryo cell very early in development

        2. Experiment replicated in other animals, pigs, monkeys

        3. Only successful if early embryo nucleus used

        4. Animal cells become committed after only few cell divisions

      3. Research in 1996 by Campbell and Wilmut produced sheep from adult nucleus

        1. Synchronized cell cycle stage of egg and donated nucleus fig 57.15

        2. Mammary cells removed from adult sheep, clone cells named "Dolly"

          1. Cells grown in tissue culture, starved just prior to implantation experiment

          2. Caused cells to pause at beginning of cell cycle

        3. Eggs from ewe enucleated

        4. Egg and nucleus surgically combined, brief electric shock applied

          1. Shock causes plasma membrane to become leaky

          2. Nucleus of mammary cell passed into egg cell

          3. Also kick starts cell cycle, resulting in cell division

        5. 30 of 277 tries showed formation of blastula stage, 29 implanted into ewes

        6. Five months later one sheep gave birth to lamb named Dolly

          1. First clone derived from fully differentiated animal cell

          2. Determination is, therefore, fully reversible

  5. Pattern Formation

    1. Encoding of Positional Information

      1. Use of positional labels in pattern formation in Drosophila

        1. Egg has initial asymmetry due to maternal mRNA deposited by nurse cells

        2. Maternal mRNA from bicoid gene marks embryo's front end

          1. mRNA translated into bicoid protein upon fertilization

          2. Diffuses through syncytial blastoderm, forming morphogen gradient

          3. Without protein no head or thorax develops, embryo is two-tailed (bicaudal)

          4. Injection of protein into anterior end causes embryo to be normal

          5. Injection at other end causes head to develop there

      2. Effect of bicoid protein occurs by activating gap genes fig 57.16

        1. Gap genes, set of six genes, map out subdivisions of embryo

        2. Hunchback gene associated with development of thorax

          1. Nanos gene associated with development of abdominal segments

          2. Nanos protein binds to hunchback mRNA, stopping its translation

          3. Hunchback only made at anterior end, away from region with nanos

          4. Hunchback diffuses backward, establishing gradient for thoracic and abdominal segments

        3. Other gap genes work in posterior regions of embryo

        4. Activate eleven sets of pair-rule genes

        5. Pair-rule genes alter every other body segment into zones

          1. One set named hairy produces seven stripe-like bands

          2. Bands divide embryo into seven zones

        6. Segment polarity genes subdivide these zones

          1. Engrailed gene divides hairy zones into anterior and posterior compartments

          2. 14 resulting compartments = 3 head + 3 thorax + 8 abdominal segments

      3. Cascade of gene activity results in segmentation of fly's body plan

        1. Activation of genes depends on morphogen diffusion in syncytial blastoderm fig 57.17

  6. Expression of Homeotic Genes

    1. Homeotic Genes Determine the Form Each Segment Will Take

      1. Code for proteins that function as transcription factors

      2. Activates a particular module of the genetic program producing body parts

    2. Homeotic Mutations

      1. Mutations in Drosophila homeotic genes

        1. Bithorax: Fly grows extra set of wings fig 57.18

        2. Antennapedia: Legs grow out of head instead of antennae

      2. Bithorax complex affect body parts of thorax and abdomen

        1. Discovered by Lewis in 1950 on third chromosome

        2. Control development of body parts in rear of thorax, all of abdomen

        3. Order of genes is order of body parts, as if genes are activated in order

          1. Genes at beginning switch on development of thorax

          2. Genes in middle affect anterior part of abdomen

          3. Genes at end affect tip of abdomen

      3. Antennapedia complex

        1. Discovered by Kaufman in 1980

        2. Governs anterior end, also serially activated fig 57.19

    3. The Homeobox

      1. Homeotic Drosophila genes typically contain homeobox sequence of amino acids

        1. Codes for homeodomain: An amino acid DNA-binding peptide domain fig 57.20

        2. Function as transcription factors, ensuring genes are transcribed at right time

        3. Bicoid and engrailed also contain homeobox sequence

      2. Distinguishes portion of genome devoted to pattern formation

    4. Evolution of Homeobox Genes

      1. Homeotic genes also found in mice and humans

        1. Genes governing positioning of body parts established early in animal evolution

        2. Similar genes function in flowering plants

      2. Drosophila gene probes identify similar sequences in myriads of organisms

        1. Mice and humans have four clusters of homeobox-containing genes

        2. Called Hox genes in mice

        3. Genes in mammals aligned in same order as segments they control fig 57.21

      3. Ordered nature of homeotic gene clusters is highly conserved in evolution fig 57.22

  7. Programmed Cell Death

    1. Many Cells in Animals Are Ultimately Destined to Die

      1. Examples: Webbing between digits, excess vertebrate neurons

      2. Presence of cells and death required for proper development

      3. Necrosis

        1. Cell death due to injury

        2. Cell swells and bursts, contents released into extracellular spaces

      4. Apoptosis

        1. Planned cell death

        2. Cell shrinks, surrounding cells absorb remains fig 57.23

    2. Gene Control of Apoptosis

      1. Animals all experience developmentally regulated suicide

        1. Example: Nematode worm

          1. Same 131 cells die during development

          2. Controlled by three genes: ced-3, ced-4, ced-9

          3. ced-3 and ced-4 constitute death program itself

          4. If either mutated, 131 cells do not die, become nervous and other tissues

          5. ced-9 represses death program

        2. Example: Human cells

          1. bax gene encode cell death program

          2. Oncogene bcl-2 represses cell death program

        3. Mechanism of apoptosis highly conserved during animal evolution

          1. Protein made by bcl-2 is 25% identical to protein made by ced-9

          2. Human blc-2 transferred into nematode with defective ced-9

          3. bcl-2 suppresses cell death program of ced-3 and ced-4

        4. Prevention of cell death by bcl-2

          1. bcl-2 may prevent damage by destroying free radicals

          2. Antioxidant: Molecule that destroys free radicals

          3. Antioxidants are almost as effective as bcl-2 in blocking apoptosis

57.3 Three model developmental systems of animals have been extensively researched
  1. The Mouse

    1. Mammalian Model System

      1. Mouse possess battery of homeotic HOX genes fig 57.24

        1. Closely related to homeotic genes of Drosophila

        2. Same genes seem to operate in same order

        3. Homeotic gene system highly conserved

      2. Creation of chimeric mice

        1. Contain cells from two genetic lines

        2. Mammalian embryos are chemically symmetrical, contain no gradients

        3. All daughter cells identical after first division

          1. Any individual cell, up to eight-cell stage, will produce complete adult

          2. Two different eight-cell cells combined to form normal adult

        4. Chimeric mice essentially have four parents

  2. The Fruit Fly

    1. Model System for Invertebrates

      1. Key organism to understand cellular mechanisms of development

        1. Examine how genes expressed early in development form adult plan fig 57.25

        2. Imaginal disks float in larva, grow into adult body parts in pupa

      2. Characteristic segmentation of adult established early in development

        1. Body divided into 17 segments, some bear jointed appendages

        2. Segments established before nuclei of blastoderm fully separated

          1. Chemical gradients established within egg by maternal material

          2. Create polarity that directs embryonic development

        3. Series of segmentation genes react to chemical gradient, subdivide embryo

          1. First divided into 4 broad areas

          2. Further divided into 7, 14 then finally 17 segments

      3. Two clusters of homeotic genes

        1. Anterior end = antennapedia complex; posterior end = bithorax complex

        2. Organization of genes corresponds to order of segments

        3. Similar set of homeotic genes govern body architecture in mice and humans

  3. The Nematode

    1. Model Describes Development in Many Animals

      1. Tiny roundworm composed of 959 somatic cells

      2. Entire genome mapped, complete DNA sequencing in progress

      3. Organism is transparent

        1. Division and migration of cells easy to follow

        2. Complete linage map determined for each cell and its divisions fig 57.26

          1. Horizontal line on map shows one round of cell division

          2. Length of line represents time between divisions

          3. End of vertical line shows one fully differentiated cell

          4. Linage map is color coded

      4. Cells are "born" after varying numbers of cell divisions

        1. Some differentiated cuticle cells "born" after 8 rounds of division

        2. Other cuticle cells require 14 divisions

        3. Pharynx cells born after 9 to 11 divisions

        4. Cells in gonads need up to 17 divisions

      5. Each worm has exact same number of cells with identical program

57.4 Aging can be considered a developmental process
  1. Theories of Aging

    1. Aging and Death Are Certainties

      1. Oldest human was 117 in 1997 fig 57.28

      2. At which individual is least likely to die is puberty, 10-15 years old fig 57.29

        1. Death rate increases rapidly after puberty

        2. Mortality rate increases exponentially, as function of increasing age

        3. Log scale plotting shows mortality increasing in straight line from 15 to 90 years

        4. Mortality rate doubles every 8 years

        5. At age 100 risk of dying reaches 50% per year

      3. Wide variety of theories to explain why animals age

    2. Accumulated Mutation Hypothesis

      1. Cells accumulate mutations as they age, lead to eventual lethal damage

        1. Somatic mutations accumulate during aging

        2. Ageing cells build up 8-hydroxyguanine, OH-group added to guanine base

      2. Little evidence that these mutations cause aging

        1. No acceleration in aging when individuals experience increased mutation rate

        2. Unlikely that there is relationship between mutation and aging

    3. Telomere Depletion Hypothesis

      1. In 1961 Hayflick demonstrated cultured cells only divided a certain number of times

        1. After 50 population doublings cell division stops fig 57.30

        2. Cell cycle blocked just before DNA replication

        3. Take sample after 20 doublings and freeze

        4. Will resume growth for 30 more doublings and stops

      2. Previous explanation for Hayflick limit

        1. Cells could only replicate chromosomes a certain number of times

        2. Enzymes copying DNA have problems with chromosomes telomeres fig 57.31

        3. As cells divided, thought that telomeres got shorter with each DNA replication

        4. After 50 replications the telomeres on the chromosome tips disappeared

      3. Research in 1997 shows that telomeres lengthen and shorten

        1. Have dynamic cycles not associated with aging

        2. Cycles depend on proteins that attach to telomeres

          1. More proteins attach to a long telomere

          2. When too many, telomere cannot function

          3. When cell divides its telomere shortens

          4. Continued to shorten till it is to short to bind enough protein to inhibit enzyme

          5. Telomere begins to lengthen again

    4. Wear and Tear Hypothesis

      1. General idea that cells wear out over time, accumulate damage till unfunctionable

        1. No inherent designed limit, but a statistical limit

        2. Disruption and damage eventually prevent cell's ability to function properly

      2. Considerable evidence that cells do accumulate damage

        1. Some evidence associated with free radicals

          1. Free radicals are atoms, molecule fragments that have unpaired electron

          2. Chemically very reactive, destructive in a cell

          3. Produced as natural by-product of oxidative metabolism

          4. Generally collected by special enzymes

        2. Damaging free radical reaction involves glucose

          1. Glucose becomes linked to proteins, called glycation

          2. Collagen and elastin are proteins often glycated

          3. Such molecules are not replaced

        3. Glycation produces mix of proteins, advanced glycosylation end products (AGEs)

          1. AGEs cross link to one another, reduce flexibility of connective tissues in joints

          2. Produce other symptoms characteristic of aging

    5. Immunological Exhaustion Hypothesis

      1. T cells respond more slowly to stimuli with age

        1. Individuals become more susceptible to infectious diseases

          1. Stock of "virgin" T cells dwindles with time

          2. More memory T cells committed to one specific antigen

        2. Depletion may be responsible for diminished immune response in older people

      2. Lower levels of interleukin-2 produced with advancing age

        1. Interleukin-2 is a T cell growth factor

        2. Pharmaceutical companies developing IL-2 cocktails against aging

    6. Gene Clock Hypothesis

      1. Some aspects of aging under direct gene control tbl 57.1

      2. Genes regulate aging like they regulate development

      3. Mutations in these genes cause premature aging in children

        1. Recessive Hutchinson-Gilford syndrome fig 57.32

          1. Growth, sexual maturation, skeletal development retarded

          2. Death by age 12 due to atherosclerosis, strokes

        2. Similar Werner's syndrome not as rare

          1. Appears in adolescence, produces death before age 50

          2. Death results from heart attack or rare connective tissue cancers

          3. Responsible gene located on short arm of chromosome 8

          4. Affects helicase enzyme involved in DNA repair

          5. Gene codes for 1432 amino acid protein, completely sequenced

          6. Four mutant alleles identified, helicases needed to unwind DNA helix

          7. Mutant helicase may fail to activate critical tumor suppressor genes

      4. Extensive aging research using C. elegans nematode

        1. Recently discovered genes affect intrinsic genetic clock

        2. Combined mutations can increase normal lifespan five times

          1. Mutations in clk-1 cause cells to divide more slowly

          2. Animal spends more time in each of phase of its life cycle

          3. Mutations in clk-2 and clk-3 have similar effects

          4. Nematodes with two mutations lived 3 to 4 times longer

        3. Slowing down life in nematodes extends life

          1. Aging may be associated with damage to cells and DNA

          2. Caused by destructive by-products of oxidative metabolism

          3. Destructive products may be produced less or more slowly with slower life

          4. Damage may be repaired more efficiently

      5. Similar genes reported in yeasts, attempting to isolate and clone them

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