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Transcript
19
Differential Gene Expression
in Development
19 Differential Gene Expression in Development
19.1 What Are the Processes of
Development?
19.2 How Is Cell Fate Determined?
19.3 What Is the Role of Gene
Expression in Development?
19.4 How Does Gene Expression
Determine Pattern Formation?
19.5 Is Cell Differentiation Reversible?
19 Differential Gene Expression in Development
Stem cells are actively dividing,
unspecialized cells that have the
potential to produce different cell types.
In stem cell therapy, stem cells are
injected into damaged tissues, where
they will differentiate and form new,
healthy tissues.
Opening Question:
What are other uses of stem cells derived
from fat?
19.1 What Are the Processes of Development?
Development: the process in which a
multicellular organism undergoes a
series of progressive changes that
characterizes its life cycle.
In its earliest stages, a plant or animal
is called an embryo.
The embryo can be protected in a
seed, an egg shell, or a uterus.
Figure 19.1 From Fertilized Egg to Adult (Part 1)
Figure 19.1 From Fertilized Egg to Adult (Part 2)
19.1 What Are the Processes of Development?
Four processes of development:
• Determination sets the fate of the cell
• Differentiation—the process by which
different types of cells arise
• Morphogenesis—organization and
spatial distribution of differentiated cells
• Growth—increase in body size by cell
division and cell expansion
19.1 What Are the Processes of Development?
Determination and differentiation occur
largely because of differential gene
expression.
Cells in the early embryo arise from
repeated mitoses and soon begin to
differ in terms of which genes are
expressed.
19.1 What Are the Processes of Development?
Morphogenesis involves differential
gene expression and the interplay of
signals between cells.
It occurs in several ways:
• Cell division
• Cell expansion in plants (position
and shape are constrained by cell
walls)
19.1 What Are the Processes of Development?
• Cell movements are important in
animals
• Apoptosis (programmed cell death);
essential in organ development
Growth occurs by increasing the
number of cells or enlargement of
existing cells.
19.1 What Are the Processes of Development?
Cell fate: which type of tissue the cell
will ultimately become.
Cell fate is usually determined quite
early in development.
The timing can be determined by
transplanting cells from one embryo to
a different region in a different
embryo.
Figure 19.2 A Cell’s Fate Is Determined in the Embryo
19.1 What Are the Processes of Development?
Cell fate determination is influenced by
gene expression and the extracellular
environment.
Determination is a commitment.
Determination is followed by
differentiation—the changes in
biochemistry, structure, and function
that result in different cell types.
19.1 What Are the Processes of Development?
During animal development, cell fate
becomes progressively more
restricted.
Cell potency: potential to differentiate
into other cell types.
• Totipotent—can differentiate into
any cell type (early embryo)
• Pluripotent—can develop into most
cell types, but cannot form new
embryos
19.1 What Are the Processes of Development?
• Multipotent—can differentiate into
several related cell types
• Unipotent—can produce only one
cell type: their own (mature
organism)
Many of these processes can be
manipulated in the laboratory.
19.2 How Is Cell Fate Determined?
How does one egg cell produce so
many different cell types?
Two processes for cell determination:
• Cytoplasmic segregation (unequal
cytokinesis)
• Induction (cell-to-cell
communication)
19.2 How Is Cell Fate Determined?
Cytoplasmic segregation:
• Factors within a zygote or egg are
not distributed evenly and end up in
different daughter cells after division.
• Polarity—developing a “top” and a
“bottom.” Can develop very early;
yolk and other factors are distributed
asymmetrically.
19.2 How Is Cell Fate Determined?
In animal development, the animal pole
is the top, the vegetal pole is the
bottom.
Sea urchin embryos
19.2 How Is Cell Fate Determined?
If the sea urchin eight-cell embryo is
cut vertically, it develops into two
small larvae.
If it is cut horizontally, the bottom
develops into a larva, the top remains
embryonic.
This indicates that the top and bottom
halves have already developed
distinct fates.
19.2 How Is Cell Fate Determined?
Model of cytoplasmic segregation:
Cytoplasmic determinants are
distributed unequally in the egg
cytoplasm.
Includes specific proteins, regulatory
RNAs, and mRNAs that play a role in
development of many organisms.
Figure 19.3 The Principle of Cytoplasmic Segregation
19.2 How Is Cell Fate Determined?
The cytoskeleton contributes to
asymmetric distribution of cytoplasmic
determinants:
• Microtubules and microfilaments
have polarity.
• Cytoskeletal elements can bind
motor proteins that transport the
cytoplasmic determinants.
19.2 How Is Cell Fate Determined?
In sea urchin eggs, a protein binds to
the growing (+) end of a microfilament
and to an mRNA encoding a
cytoplasmic determinant.
As the microfilament grows toward one
end of the cell, it carries the mRNA
along with it.
The asymmetrical distribution of the
mRNA leads to a similar distribution of
the protein it encodes.
19.2 How Is Cell Fate Determined?
Induction: cells in a developing
embryo influence one another’s
developmental fate via chemical
signals and signal transduction
mechanisms.
19.2 How Is Cell Fate Determined?
Development of the lens in the
vertebrate eye:
The forebrain bulges out to form optic
vesicles, which come in contact with
cells at the surface of the head. These
surface cells ultimately become the
lens.
The optic vesicle must contact the
surface cells, or the lens will not
develop.
Figure 19.4 Embryonic Inducers in Vertebrate Eye Development
19.2 How Is Cell Fate Determined?
The surface cells receive a signal, or
inducer, from the optic vesicles.
Inducers trigger sequences of gene
expression in the responding cells.
How genes are switched on and off to
govern development is studied using
model organisms.
19.2 How Is Cell Fate Determined?
Vulval development in Caenorhabditis
elegans:
Adults are hermaphroditic; eggs are
laid through a ventral pore called the
vulva.
Figure 19.5 Induction during Vulval Development in Caenorhabditis elegans (Part 1)
19.2 How Is Cell Fate Determined?
During development, one cell, the
anchor cell, induces the vulva to form
from six cells on the ventral surface.
Two signals are involved: the primary
(1) and secondary (2) inducers.
The concentration gradient of the
primary inducer (LIN-3) is key. It is
produced by the anchor cell and
diffuses out to form the gradient.
Figure 19.5 Induction during Vulval Development in Caenorhabditis elegans (Part 2)
19.2 How Is Cell Fate Determined?
The inducers control activation or
inactivation of genes through signal
transduction cascades.
This differential gene expression leads
to cell differentiation.
19.3 What Is the Role of Gene Expression in Development?
All cells in an organism have the same
genes, but each cell expresses only
certain ones.
The mechanisms that control gene
expression during cell fate
determination and differentiation work
at the level of transcription.
19.3 What Is the Role of Gene Expression in Development?
Cell fate determination can occur by
induction.
When an inducer molecule binds to a
receptor on the cell surface, a signal
transduction pathway leads to
activation of transcription factors.
Figure 19.6 Induction
19.3 What Is the Role of Gene Expression in Development?
Development is often controlled by
these kinds of molecular switches,
which allow a cell to proceed down
one of two alternative paths.
In nematodes, LIN-3 is a growth factor;
it binds to receptors on vulva
precursor cells, starting a signal
transduction pathway that includes
Ras protein and MAP kinases.
19.3 What Is the Role of Gene Expression in Development?
The gene for b-globin (part of
hemoglobin) is expressed in red blood
cells.
This gene exists in other cells, but is
not expressed. This can be shown
using nucleic acid hybridization.
A probe for the b-globin gene will find
its complement in DNA from brain
cells but not in mRNA from brain cells.
19.3 What Is the Role of Gene Expression in Development?
Differentiation in muscle cells:
Muscle precursor cells come from an
embryonic layer called the mesoderm.
When these cells commit to becoming
muscle cells, they stop dividing.
In most embryonic cells, cell division
and cell differentiation are mutually
exclusive.
19.3 What Is the Role of Gene Expression in Development?
• Cell signaling activates the gene for
a transcription factor called MyoD.
• MyoD activates the gene for p21, an
inhibitor of cyclin-dependent kinases
that normally stimulate the cell cycle.
• The cell cycle stops so that
differentiation can begin.
Figure 19.7 Transcription and Differentiation in the Formation of Muscle Cells
19.4 How Does Gene Expression Determine Pattern Formation?
Pattern formation: The process that
results in the spatial organization of
tissues and organisms.
• Linked to morphogenesis, creation of
body form
Morphogenesis involves cell division
and differentiation, as well as
apoptosis (programmed cell death).
19.4 How Does Gene Expression Determine Pattern Formation?
In human embryos, connective tissue
links the fingers and toes. Later, the
cells between the digits die.
In-Text Art, Ch. 19, p. 399
19.4 How Does Gene Expression Determine Pattern Formation?
Model organisms are used to study
apoptosis.
Mutants with altered cell death
phenotypes are used to identify the
genes and proteins involved.
19.4 How Does Gene Expression Determine Pattern Formation?
C. elegans produces exactly 1,090
somatic cells as it develops, but 131
of those cells die.
The sequential activation of two
proteins controls this cell death.
A third gene codes for an inhibitor of
apoptosis in cells not programmed to
die.
Figure 19.8 Pathways for Apoptosis
19.4 How Does Gene Expression Determine Pattern Formation?
A similar system controls apoptosis in
human development.
The proteins are similar to those of C.
elegans.
The conservation of this pathway in
evolution indicates its importance:
Mutations are harmful, and evolution
selects against them.
19.4 How Does Gene Expression Determine Pattern Formation?
Flowers are composed of four organ
types (sepals, petals, stamens,
carpels) arranged around a central
axis in whorls.
In Arabidopsis thaliana, flowers
develop from a meristem
(undifferentiated, rapidly growing
cells) at the growing point on the
stem.
Figure 19.9 Organ Identity Genes in Arabidopsis Flowers (Part 1)
19.4 How Does Gene Expression Determine Pattern Formation?
The identity of each whorl is
determined by organ identity genes:
• Class A genes, expressed in sepals
and petals
• Class B genes, expressed in petals
and stamens
• Class C genes, expressed in
stamens and carpels
19.4 How Does Gene Expression Determine Pattern Formation?
The genes code for transcription
factors, which are active as dimers.
Dimer composition determines which
whorl will develop.
The A, B, and C proteins, and many
other plant transcription factors, have
a DNA-binding domain called the
MADS box.
Figure 19.9 Organ Identity Genes in Arabidopsis Flowers (Part 2)
19.4 How Does Gene Expression Determine Pattern Formation?
Two lines of experimental evidence
support this model for floral organs:
• Loss-of-function mutations—
mutation in A results in no sepals or
petals
• Gain-of-function mutations—
promoter for C can be coupled to A,
resulting in only sepals and petals.
(Homeotic mutation: one organ is
replaced by another.)
19.4 How Does Gene Expression Determine Pattern Formation?
A protein called LEAFY controls
transcription of organ identity genes.
Plants with loss-of-function mutations
of LEAFY do not produce flowers.
Transgenic orange trees, expressing
the LEAFY gene coupled to a strongly
expressed promoter, flower and fruit
years earlier than normal trees.
19.4 How Does Gene Expression Determine Pattern Formation?
Fate of a cell is often determined by
where the cell is.
Positional information often comes in
the form of an inducer called a
morphogen, which diffuses from one
group of cells to another, setting up a
concentration gradient.
19.4 How Does Gene Expression Determine Pattern Formation?
A morphogen:
• Directly affects target cells
• Different concentrations of the
morphogen cause different effects
The “French flag model” explains
morphogens and can be applied to
differentiation of the vulva in C.
elegans.
Figure 19.10 The French Flag Model
19.4 How Does Gene Expression Determine Pattern Formation?
Vertebrate limb development also
follows the French flag model.
Cells that develop into digits must
receive positional information.
Cells in the zone of polarizing activity
(ZPA) secrete a morphogen called
Sonic hedgehog (Shh). It forms a
gradient that determines the
posterior–anterior axis.
Figure 19.11 Specification of the Vertebrate Limb and the French Flag Model
19.4 How Does Gene Expression Determine Pattern Formation?
Morphogens have been studied in the
fruit fly Drosophila melanogaster.
The head, thorax, and abdomen are
each made of several fused segments;
different body parts arise from different
segments (e.g., wings and antennae).
Segments appear early in development,
in the early larval stage. Cell fates have
already been determined.
19.4 How Does Gene Expression Determine Pattern Formation?
In the first 12 mitotic divisions there is no
cytokinesis, forming a multinucleate embryo.
Morphogens can diffuse easily in the embryo.
In-Text Art, Ch. 19, p. 402
19.4 How Does Gene Expression Determine Pattern Formation?
The steps of cell determination were
studied using experimental genetics:
• Developmental mutations were
identified
• Mutants were compared with wild
types to identify genes and proteins
• Experiments confirmed gene and
protein functions
19.4 How Does Gene Expression Determine Pattern Formation?
The experiments revealed a cascade of
gene expression. Three gene classes
are involved:
• Maternal effect genes set up the
major axes of the egg.
• Segmentation genes determine
boundaries and polarity of each
segment.
• Hox genes determine which organ
will be made at a given location.
19.4 How Does Gene Expression Determine Pattern Formation?
Maternal effect genes
Transcribed in cells of the mother’s
ovary; the mRNAs are passed to the
egg.
Bicoid and nanos help determine the
anterior–posterior axis of the embryo.
Figure 19.12 Concentrations of Bicoid and Nanos Proteins
Determine the Anterior–Posterior Axis (Part 1)
19.4 How Does Gene Expression Determine Pattern Formation?
mRNA from a third gene, hunchback, is
distributed evenly in the embryo at
first, but Nanos inhibits its translation,
while Bicoid stimulates it—setting up
a gradient of Hunchback.
Figure 19.12 Concentrations of Bicoid and Nanos Proteins
Determine the Anterior–Posterior Axis (Part 2)
19.4 How Does Gene Expression Determine Pattern Formation?
How were these pathways determined?
• Bicoid mutants produce larvae with
no head and no thorax.
Cytoplasm from the anterior end of
wild-type eggs will produce normal
larvae.
• Cytoplasm from the anterior end of
wild-type eggs, injected into
posterior end of another egg, will
produce anterior structures there.
19.4 How Does Gene Expression Determine Pattern Formation?
• Nanos mutants produce larvae with
no abdomen.
Cytoplasm from the posterior end of
wild-type eggs will produce normal
larvae.
19.4 How Does Gene Expression Determine Pattern Formation?
Segmentation genes
Three classes of genes act in
sequence:
• Gap genes organize broad areas;
mutations result in omission of
several body segments.
• Pair rule genes divide embryo into
units of two segments each;
mutations result in every other
segment missing.
19.4 How Does Gene Expression Determine Pattern Formation?
• Segment polarity genes determine
boundaries and anterior–posterior
organization in individual segments.
Mutations result in posterior
structures being replaced by
reversed (mirror-image) anterior
structures.
Figure 19.13 A Gene Cascade Controls Pattern Formation in the Drosophila Embryo
19.4 How Does Gene Expression Determine Pattern Formation?
Hox genes encode transcription
factors that are expressed in different
combinations along the length of the
embryo. They determine cell fate in
each segment.
Hox genes are on chromosome 3 in the
same order as the segments whose
functions they determine.
Figure 19.14 Hox Genes in Drosophila Determine Segment Identity
19.4 How Does Gene Expression Determine Pattern Formation?
Hox genes are shared by all animals.
They are homeotic genes—a mutation
can result in one organ being replaced
by another.
19.4 How Does Gene Expression Determine Pattern Formation?
Clues to hox gene function came from
homeotic mutants.
Antennapedia mutation—legs grow in
place of antennae.
Bithorax mutation—an extra pair of
wings grow.
Figure 19.15 A Homeotic Mutation in Drosophila
19.4 How Does Gene Expression Determine Pattern Formation?
Hox genes have a 180 base pair
sequence called the homeobox. It
encodes a 60 amino acid sequence
called the homeodomain.
The homeodomain binds to specific
DNA sequences in the promoters of
target genes.
19.4 How Does Gene Expression Determine Pattern Formation?
This homeodomain is found in
transcription factors that regulate
development in many other animals
with an anterior–posterior axis.
19.5 Is Cell Differentiation Reversible?
A zygote is totipotent—it can give rise
to every cell type in the organism.
As development proceeds, cells
become determined and lose their
totipotency.
But most differentiated cells still contain
the entire genome and still have the
capacity for totipotency.
19.5 Is Cell Differentiation Reversible?
In 1958, experiments showed that an
entire carrot plant could be cloned
from differentiated carrot root cells.
This showed that the root cell
contained a functional, entire genome.
In forestry and agriculture, many plants
are produced as clones from a single
cell, to produce uniform
characteristics.
Figure 19.16 Cloning a Plant
19.5 Is Cell Differentiation Reversible?
In animals, early embryonic cells have
totipotency. This permits genetic
screening and some types of assisted
reproductive technologies.
An embryo can be isolated and one or
a few cells removed and examined for
certain genetic conditions. The
remaining cells can develop into a
complete embryo and be implanted
into the mother’s uterus.
19.5 Is Cell Differentiation Reversible?
An isolated animal embryo cell will not
develop into a complete organism, but
the nucleus has the potential to do
this.
Nuclear transfer experiments show that
genetic material from a single cell can
be used to clone animals.
Frogs were cloned in the 1950s.
19.5 Is Cell Differentiation Reversible?
These cloning experiments indicated
that:
• No genetic information is lost as the
cell passes through developmental
stages (genomic equivalence).
• The cytoplasmic environment can
modify the cell’s fate.
19.5 Is Cell Differentiation Reversible?
In 1996, the first mammal was cloned
by somatic cell nuclear transfer.
A somatic cell from one sheep (the
donor) was fused with an enucleated
egg from another sheep. The donor’s
cell was fully differentiated.
After the fused cell began divisions, it
was implanted into the uterus of a
third sheep.
Figure 19.17 Cloning a Mammal
Working with Data 19.1: Cloning a Mammal
Cloning of Dolly the sheep
demonstrated that under appropriate
circumstances, animal cells are
totipotent.
But there is a danger of premature
aging. Dolly developed severe
arthritis; premature aging may be due
to shortened telomeres in her cells.
Working with Data 19.1: Cloning a Mammal
Question 1:
In addition to mammary epithelium
(ME) cells, Wilmut’s team also
attempted cloning by nuclear transfer
from fetal fibroblasts (FB) and
embryo-derived cells (EC).
What can you conclude about the
efficiency of this cloning process?
Working with Data 19.1, Table 1
Working with Data 19.1: Cloning a Mammal
Question 2:
Compare the efficiencies of cloning
using nuclear donors from different
sources.
What can you conclude about the
ability of different nuclei to be
reprogrammed?
Working with Data 19.1: Cloning a Mammal
Question 3:
Polymorphic DNA markers were used
to analyze Dolly’s genetic make-up.
The data for four short tandem repeat
(STR) markers (FCB 11, FCB 304,
MAF 33, and MAF 209) are shown in
the figure.
Working with Data 19.1: Cloning a Mammal
In the electrophoresis gels, different
genotypes produce DNA bands of
different sizes. A sample of Dolly’s
DNA was compared with samples
from her nuclear donor (mammary
cells from a Finn Dorset ewe) and
from the recipient (her surrogate
mother, a Scottish Blackface ewe).
Working with Data 19.1, Figure A
Working with Data 19.1: Cloning a Mammal
Are the DNA bands from Dolly the
same sizes as those from her nuclear
donor or from her surrogate mother?
What does this indicate about Dolly’s
genetic makeup?
19.5 Is Cell Differentiation Reversible?
Cloning of Dolly the sheep showed that
a fully differentiated cell from a mature
animal can revert to a totipotent state.
Many other species have since been
cloned by nuclear transfer.
19.5 Is Cell Differentiation Reversible?
Reasons to clone animals:
• Increase number of valuable
animals, such as transgenic animals
carrying genes with therapeutic
properties.
Example: a cow that was genetically
engineered to make human growth
hormone in milk has been cloned to
produce the hormone for children
with growth hormone deficiency.
19.5 Is Cell Differentiation Reversible?
• Preservation of endangered species:
Cloning may be the only way to save
endangered species with low
reproduction rates, such as pandas.
• Preservation of pets
19.5 Is Cell Differentiation Reversible?
Stem cells: rapidly dividing,
undifferentiated cells that can
differentiate into several cell types.
In plants, stem cells are in the
meristems
In mammals, stem cells occur in
tissues that require frequent
replacement—skin, blood, intestinal
lining.
19.5 Is Cell Differentiation Reversible?
Stem cells in adult animals are
multipotent: the daughter cells
differentiate into only a few cell types.
In the bone marrow, hematopoietic
stem cells produce blood cells,
mesenchymal stem cells produce
bone and connective tissue cells.
19.5 Is Cell Differentiation Reversible?
Multipotent stem cells differentiate “on
demand.”
Bone marrow stem cells differentiate in
response to specific growth factors.
This is the basis of a cancer therapy
called hematopoietic stem cell
transplantation (HSCP).
19.5 Is Cell Differentiation Reversible?
Therapies that kill cancer cells can also
kill other rapidly dividing cells such as
bone marrow stem cells.
The stem cells are removed, stored
during the therapy, then returned to
the bone marrow.
The stored stem cells retain their ability
to differentiate.
Figure 19.18 Stem Cell Transplantation
19.5 Is Cell Differentiation Reversible?
Adjacent cells can influence stem cell
differentiation.
Experiments show that damaged
tissues can heal more effectively if
stem cells are injected into the tissue.
The mechanism is unclear; the stem
cells may be able to insert into the
tissue and differentiate, or signals
from the stem cells induce tissue
regeneration.
19.5 Is Cell Differentiation Reversible?
In the embryonic stage called the
blastocyst, a group of cells is
pluripotent—they can differentiate into
most cell types, but cannot give rise to
a complete organism.
In mice, these embryonic stem cells
(ESCs) can be removed from the
blastocyst and grown in laboratory
culture almost indefinitely.
19.5 Is Cell Differentiation Reversible?
ESCs can be induced to differentiate in
the laboratory by specific signals.
Treatment with a vitamin A derivative
causes them to form neurons; other
growth factors induce them to form
blood cells.
19.5 Is Cell Differentiation Reversible?
ESC cultures have potential as sources
of differentiated cells to repair specific
tissues, such as a damaged pancreas
in diabetes or a brain that
malfunctions in Parkinson’s disease.
19.5 Is Cell Differentiation Reversible?
ESCs can be harvested from human
embryos conceived by in vitro
fertilization, with consent of the
donors. However:
• Some people object to the
destruction of human embryos for
this purpose.
• The stem cells could provoke an
immune response in a recipient.
19.5 Is Cell Differentiation Reversible?
Another approach: induced
pluripotent stem cells (iPS cells)
can be made from skin cells.
Genes essential to the undifferentiated
state and function of stem cells were
identified.
These genes were coupled to highly
expressing promoters and injected
into skin cells.
Figure 19.19 Two Ways to Obtain Pluripotent Stem Cells
19.5 Is Cell Differentiation Reversible?
The skin cells were then pluripotent
and could differentiate into many cell
types.
iPS cells can be made from a patient’s
own skin cells, so immune responses
are avoided.
These therapies have been tested in
animals.
17 Answer to Opening Question
In the United States, veterinarians use
multipotent stem cells derived from fat
to treat injuries and osteoarthritis in
animals.
In the operating room, large quantities
of stem cells can be isolated from
human patients and used immediately
to repair tissues, for example, after
surgery for breast cancer.