Transcript Chap 47 - midpac.edu

Chap 47
Animal Development
• The Acrosomal Reaction.
– Acrosomal reaction: when exposed to the jelly
coat the sperm’s acrosome discharges it contents by
exocytosis.
• Hydrolytic enzymes enable the acrosomal process to
penetrate the egg’s jelly coat.
• The tip of the acrosomal process adheres
to the vitelline layer just external to the
egg’s plasma membrane.
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– The sperm and egg plasma membranes fuse and a single
sperm nucleus enter the egg’s cytoplasm.
• Na+ channels in the egg’s plasma membrane opens.
– Na+ flows into the egg and the membrane depolarizes: fast block to
polyspermy.
Na+
• The Cortical Reaction.
– Fusion of egg and sperm plasma membranes triggers a
signal-transduction pathway.
•  IP3 and DAG are produced. IP3 acts as a second messenger and
opens ligand-gated channels in the ER and the Ca2+ released
stimulates the opening of other channels.
• Ca2+ from the eggs ER is released into the cytosol and propagates as
a wave across the fertilized egg – cortical granules release contents
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• DAG and IP3 are created when a phospholipase
cleaves a membrane phospholipid PIP2.
– Phospholipase may be activated by a G protein or a
tyrosine-kinase receptor.
– IP3 activates a gated-calcium channel, releasing Ca2+.
Fig. 11.15
The Cortical Reaction
• Fusion of egg and sperm also initiates the
cortical reaction
– Inducing a rise in Ca2+ that stimulates cortical
granules to release their contents outside the egg
EXPERIMENT
A fluorescent dye that glows when it binds free Ca2+ was injected into unfertilized sea urchin eggs. After sea urchin
sperm were added, researchers observed the eggs in a fluorescence microscope.
500 m
RESULTS
10 sec after
fertilization
1 sec before
fertilization
Point of
sperm
entry
Figure 47.4
20 sec
30 sec
Spreading wave
of calcium ions
CONCLUSION
The release of Ca2+ from the endoplasmic reticulum into the cytosol at the site of sperm entry triggers the release
of more and more Ca2+ in a wave that spreads to the other side of the cell. The entire process takes about 30 seconds.
1 Contact. The
sperm cell
contacts the
egg’s jelly coat,
triggering
exocytosis from the
sperm’s acrosome.
2 Acrosomal reaction. Hydrolytic 3 Contact and fusion of sperm
and egg membranes. A hole
enzymes released from the
is made in the vitelline layer,
acrosome make a hole in the
allowing contact and fusion of
jelly coat, while growing actin
both gamete plasma membranes.
filaments form the acrosomal
The membrane becomes
process. This structure protrudes
depolarized, resulting in the
from the sperm head and
penetrates the jelly coat, binding
fast block to polyspermy.
to receptors in the egg cell
membrane that extend through
the vitelline layer.
4 Entry of
sperm nucleus.
• The acrosomal reaction
Sperm plasma
membrane
5
Cortical reaction. Fusion of the
gamete membranes triggers an
increase of Ca2+ in the egg’s
cytosol, causing cortical granules
in the egg to fuse with the plasma
membrane and discharge their
contents. This leads to swelling of the
perivitelline space, hardening of the
vitelline layer, and clipping of
sperm-binding receptors. The resulting
fertilization envelope is the slow block
to polyspermy.
Sperm
nucleus
Acrosomal
process
Basal body
(centriole)
Sperm
head
Actin
1
Acrosome
Jelly coat
Sperm-binding
receptors
Figure 47.3
Fertilization
envelope
Ca++
Fused plasma
Cortical membranes
granule
Perivitelline
Hydrolytic enzymes
space
2
3
Cortical granule
membrane
Vitelline layer
Egg plasma
membrane
EGG CYTOPLASM
• Fertilization in Mammals.
• Capacitation, a function of the female reproductive
system, enhances sperm function.
– A capacitated
sperm migrates
through a layer
of follicle cells
before it reaches
the zona pellucida.
– Binding of
the sperm cell
induces an
acrosomal
reaction similar
to that seen in the
sea urchin.
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Cortical reaction
forms slow
block
Fig. 47.5
• Enzymes from the acrosome enable the sperm cell to
penetrate the zona pellucida and fuse with the egg’s
plasma membrane.
– The entire sperm enters the egg.
– The egg membrane depolarizes: functions as a fast block to
polyspermy.
– A cortical reaction occurs.
• Enzymes from cortical granules catalyze
alterations to the zona pellucida:
functions as a slow block to polyspermy.
Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings
– The envelopes of both the egg and sperm nuclei
disperse.
• The chromosomes from the two gametes share a common
spindle apparatus during the first mitotic division of the
zygote.
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3. Cleavage partitions the zygote
into many smaller cells
• Cleavage follows fertilization.
– The zygote is partitioned into blastomeres.
• Each blastomere contains different regions of the undivided
cytoplasm and thus different cytoplasmic determinants.
Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings
Fig. 47.6
• Cleavage partitions the cytoplasm of one
large cell
– Into many smaller cells called blastomeres
(a) Fertilized egg. Shown here is the (b) Four-cell stage. Remnants of the (c) Morula. After further cleavage
mitotic spindle can be seen
divisions, the embryo is a
zygote shortly before the first
between
the
two
cells
that
have
multicellular ball that is still
cleavage division, surrounded
just
completed
the
second
surrounded by the fertilization
by the fertilization envelope.
cleavage
division.
envelope. The blastocoel cavity
The nucleus is visible in the
has begun to form.
center.
Figure 47.7a–d
(d) Blastula. A single layer of cells
surrounds a large blastocoel
cavity. Although not visible here,
the fertilization envelope is still
present; the embryo will soon
hatch from it and begin swimming.
– Except for mammals, most animals have both eggs
and zygotes with a definite polarity.
• Thus, the planes of division follow a specific pattern
relative to the poles of the zygote.
• Polarity is defined by the heterogeneous distribution of
substances such as mRNA, proteins, and yolk.
– Yolk is most concentrated at the vegetal pole and least
concentrated at the animal pole.
• In some animals, the animal pole defines
the anterior end of the animal.
Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings
• In amphibians a rearrangement of the egg
cytoplasm occurs at the time of fertilization.
• The plasma membrane
and cortex rotate
toward the point
of sperm entry.
– The gray crescent
is exposed and marks
the dorsal surface
of the embryo.
• Cleavage occurs more
rapidly in the animal
pole than in the
vegetal pole.
Fig. 47.7
Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings
Sperm’s basal
body turns into
centrosome
Forms dorsal
side of animal
First cleavage is perpendicular
through gray crescent area
Axes of body
established
before first
cleavage
• In both sea urchins and frogs first two
cleavages are vertical.
• The third division is horizontal.
• The result is an eight-celled embryo with two
tiers of four cells.
Fig. 47.8a
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• Continued cleavage produces the morula.
Fig. 47.8b
Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings
• A blastocoel forms within the morula 
blastula
Fig. 47.8d
Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings
• In animals with less yolk there is complete
division of the egg: holoblastic cleavage.
Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings
Yolk impedes
cleavage
establishing
vegetal pole
• Gastrulation in a
sea urchin
– Produces an
embryo with a
primitive gut and
three germ layers
• The mechanics of gastrulation in a frog
– Are more complicated than in a sea urchin
1 Gastrulation begins when a small indented crease,
the dorsal lip of the blastopore, appears on one
side of the blastula. The crease is formed by cells
changing shape and pushing inward from the
surface (invagination). Additional cells then roll
inward over the dorsal lip (involution) and move into
the interior, where they will form endoderm and
mesoderm. Meanwhile, cells of the animal pole, the
future ectoderm, change shape and begin spreading
over the outer surface.
SURFACE VIEW
Animal pole
CROSS SECTION
Blastocoel
Dorsal lip
Vegetal pole of blastopore Blastula
Blastocoel
shrinking
2 The blastopore lip grows on both sides of the
embryo, as more cells invaginate. When the sides
of the lip meet, the blastopore forms a circle that
becomes smaller as ectoderm spreads downward
over the surface. Internally, continued involution
expands the endoderm and mesoderm, and the
archenteron begins to form; as a result, the
blastocoel becomes smaller.
3 Late in gastrulation, the endoderm-lined archenteron
has completely replaced the blastocoel and the
three germ layers are in place. The circular blastopore
surrounds a plug of yolk-filled cells.
Blastocoel
remnant
Dorsal lip
of blastopore
Archenteron
Ectoderm
Mesoderm
Endoderm
Key
Future ectoderm
Figure 47.12
Future mesoderm
Future endoderm
Yolk plug
Yolk plug
Gastrula
• Gastrulation
in the chick
Epiblast
– Is affected by the large amounts of yolk in the egg
Future
ectoderm
Primitive
streak
Migrating
cells
(mesoderm)
Endoderm
Hypoblast
YOLK
Figure 47.13
Organogenesis
• Various regions of the three embryonic
germ layers
– Develop into the rudiments of organs during the
process of organogenesis
• Early in vertebrate organogenesis
– The notochord forms from mesoderm and the
neural plate forms from ectoderm
Neural folds
LM
1 mm
Neural
fold
Neural
plate
Notochord
Ectoderm
Mesoderm
Endoderm
Archenteron
(a)
Neural plate formation. By the time
shown here, the notochord has
developed from dorsal mesoderm,
and the dorsal ectoderm has
thickened, forming the neural plate,
in response to signals from the
notochord. The neural folds are
the two ridges that form the lateral
edges of the neural plate. These
are visible in the light micrograph
of a whole embryo.
Figure 47.14a
• The neural plate soon curves inward
– Forming the neural tube
Neural
fold
Neural plate
Neural crest
Outer layer
of ectoderm
Neural crest
Neural tube
(b)
Figure 47.14b
Formation of the neural tube.
Infolding and pinching off of the
neural plate generates the neural tube.
Note the neural crest cells, which will
migrate and give rise to numerous
structures.
Organogenesis involves folds, splits, and dense clustering of cells
• Mesoderm lateral to the notochord
– Forms blocks called somites
• Lateral to the somites
– The mesoderm splits to form the coelom
Eye
SEM
Somites
Neural tube
Notochord
Tail bud
1 mm
Neural
crest
Coelom
Somite
Archenteron
(digestive cavity)
(c)
Somites. The drawing shows an embryo
after completion of the neural tube. By
this time, the lateral mesoderm has
begun to separate into the two tissue
layers that line the coelom; the somites,
formed from mesoderm, flank the
notochord. In the scanning electron
micrograph, a side view of a whole
embryo at the tail-bud stage, part of the
ectoderm has been removed, revealing
the somites, which will give rise to
segmental structures such as vertebrae
and skeletal muscle.
Figure 47.14c
• Organogenesis in the chick
– Is quite similar to that in the frog
Eye
Forebrain
Neural tube
Notochord
Somite
Heart
Coelom
Archenteron
Endoderm
Lateral fold
Blood
vessels
Mesoderm
Ectoderm
YOLK
Yolk stalk
Somites
Yolk sac
Form extraembryonic
membranes
(a) Early organogenesis. The archenteron forms when lateral folds
pinch the embryo away from the yolk. The embryo remains open
to the yolk, attached by the yolk stalk, about midway along its length,
as shown in this cross section. The notochord, neural tube, and
somites subsequently form much as they do in the frog.
Figure 47.15a, b
Neural tube
(b) Late organogenesis. Rudiments of most
major organs have already formed in this
chick embryo, which is about 56 hours old
and about 2–3 mm long (LM).
Meroblastic
cleavage due
to yolk
In birds the yolk is
so plentiful that it
restricts cleavage
to the animal pole:
meroblastic
cleavage.
• Many different structures
– Are derived from the three embryonic germ
layers during organogenesis
ECTODERM
• Epidermis of skin and its
derivatives (including sweat
glands, hair follicles)
• Epithelial lining of mouth
and rectum
• Sense receptors in
epidermis
• Cornea and lens of eye
• Nervous system
• Adrenal medulla
• Tooth enamel
• Epithelium or pineal and
pituitary glands
Figure 47.16
MESODERM
• Notochord
• Skeletal system
• Muscular system
• Muscular layer of
stomach, intestine, etc.
• Excretory system
• Circulatory and lymphatic
systems
• Reproductive system
(except germ cells)
• Dermis of skin
• Lining of body cavity
• Adrenal cortex
ENDODERM
• 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
Develops into embryo
Will form fetal portion of placenta
Forms yolk sac
The Cytoskeleton, Cell Motility, and
Convergent Extension
• Changes in the shape of a cell
– Usually involve reorganization of the
cytoskeleton
• The formation of the neural tube
– Is affected by microtubules and microfilaments
Ectoderm
Neural
plate
1 Microtubules help elongate
the cells of the neural plate.
2 Microfilaments at the dorsal
end of the cells may then contract,
deforming the cells into wedge shapes.
3 Cell wedging in the opposite
direction causes the ectoderm to
form a “hinge.”
4 Pinching off of the neural plate
forms the neural tube.
Figure 47.19
• The cytoskeleton also drives cell migration, or
cell crawling
– The active movement of cells from one place to
another
• In gastrulation, tissue invagination
– Is caused by changes in both cell shape and cell
migration
• Cell crawling is also involved in convergent
extension
– A type of morphogenetic movement in which
the cells of a tissue become narrower and
longer
Figure 47.20
Convergent Extension
cell crawling results in morphogenic movement
may involve the ECM (extracellular matrix) which is the mixture of
glycoproteins outside the plasma membrane
ECM fibers may acts as tracks that act as routes for migrating cells in
morphogenic movement or they inhibit migration in certain directions
Example
fibronectin lines the the roof of the
blastocoel and acts as a guide to a
sheet of migrating mesoderm cells.
Roles of the Extracellular Matrix and
Cell Adhesion Molecules
• Fibers of the extracellular matrix
– May function as tracks, directing migrating
cells along particular routes
• Several kinds of glycoproteins, including
fibronectin
– Promote cell migration by providing specific
molecular anchorage for moving cells
EXPERIMENT Researchers placed a strip of fibronectin on an artificial underlayer. After positioning
migratory neural crest cells at one end of the strip, the researchers observed the movement of the cells
in a light microscope.
RESULTS
In this micrograph, the dashed lines indicate the edges of the fibronectin layer. Note
that cells are migrating along the strip, not off of it.
Direction of migration
50 µm
Figure 47.21
CONCLUSIONFibronectin helps promote cell migration, possibly by providing anchorage for the
migrating cells.
• Cell adhesion molecules
– Also contribute to cell migration and stable
tissue structure
• One important class of cell-to-cell adhesion
molecule is the cadherins
– Which are important in the formation of the
frog blastula
EXPERIMENT
Researchers injected frog eggs with nucleic acid complementary to the mRNA encoding
a cadherin known as EP cadherin. This “antisense” nucleic acid leads to destruction of the mRNA for
normal EP cadherin, so no EP cadherin protein is produced. Frog sperm were then added to control
(noninjected) eggs and to experimental (injected) eggs. The control and experimental embryos that
developed were observed in a light microscope.
RESULTS
As shown in these micrographs, fertilized control eggs developed into normal blastulas,
but fertilized experimental eggs did not. In the absence of EP cadherin, the blastocoel did not form properly,
and the cells were arranged in a disorganized fashion.
Control embryo
Experimental embryo
Figure 47.22
CONCLUSION
Proper blastula formation in the frog requires EP cadherin.
CAM or cell adhesion molecules are
glycoproteins that help regulate
morphogenic movements and tissue
building
Cadherin is a CAM that is
produced at specific times and
locations during development
EP calhedrin can interfere with
the blastula formation in frogs
• Concept 47.3: The developmental fate of cells
depends on their history and on inductive signals
• Coupled with morphogenetic changes
– Development also requires the timely differentiation
of many kinds of cells at specific locations
Two general principles
Underlie differentiation during embryonic
development
• First, during early cleavage divisions
– Embryonic cells must somehow become different
from one another
• Second, once initial cell asymmetries are set up
– Subsequent interactions among the embryonic cells
influence their fate, usually by causing changes in
gene expression
Somites will give
rise to
segmental
structures such
as vertebrae and
serially arranged
skeletal muscles
Name the 3
different germ
layers
Establishing Cellular
Asymmetries
• To understand at the molecular level how
embryonic cells acquire their fates
– It is helpful to think first about how the basic
axes of the embryo are established
The Axes of the Basic Body Plan
• In nonamniotic vertebrates
– Basic instructions for establishing the body
axes are set down early, during oogenesis or
fertilization
• In amniotes, local environmental
differences
– Play the major role in establishing initial
differences between cells and, later, the body
axes
Restriction of Cellular Potency
• In many species that have cytoplasmic
determinants
– Only the zygote is totipotent, capable of
developing into all the cell types found in the
adult
• Unevenly distributed cytoplasmic
determinants in the egg cell
– Are important in establishing the body axes
– Set up differences in blastomeres resulting from
cleavage
EXPERIMENT
1
Gray
crescent
Left (control):
Fertilized
salamander eggs
were allowed to
divide normally,
resulting in the
gray crescent being
evenly divided
between the two
blastomeres.
Right (experimental):
Fertilized eggs were
constricted by a
thread so that the
first cleavage plane
restricted the gray
crescent to one
blastomere.
Gray
crescent
2 The two blastomeres were
then separated and
allowed to develop.
Normal
Belly
piece
Normal
RESULTS
Blastomeres that receive half or all of the gray crescent develop into normal embryos, but a blastomere
that receives none of the gray crescent gives rise to an abnormal embryo without dorsal structures. Spemann called it a
“belly piece.”
CONCLUSION
The totipotency of the two blastomeres normally formed during the first cleavage division depends on
cytoplasmic determinants localized in the gray crescent.
Figure 47.24
• As embryonic development proceeds
– The potency of cells becomes progressively
more limited in all species
Cell Fate Determination and Pattern
Formation by Inductive Signals
• Once embryonic cell division creates cells
that differ from each other
– The cells begin to influence each other’s fates
by induction
The “Organizer” of Spemann
and Mangold
• Based on the results of their most famous
experiment
– Spemann and Mangold concluded that the
dorsal lip of the blastopore functions as an
organizer of the embryo
• The organizer initiates a chain of inductions
– That results in the formation of the notochord,
the neural tube, and other organs
EXPERIMENT Spemann and Mangold transplanted a piece of the dorsal lip of a pigmented newt gastrula to the
ventral side of the early gastrula of a nonpigmented newt.
Pigmented gastrula
(donor embryo)
Dorsal lip of
blastopore
Nonpigmented gastrula
(recipient embryo)
RESULTS
During subsequent development, the recipient embryo formed a second notochord and neural tube in
the region of the transplant, and eventually most of a second embryo. Examination of the interior of the double embryo
revealed that the secondary structures were formed in part from host tissue.
Primary embryo
Primary
structures:
Secondary
structures:
Notochord (pigmented cells)
Secondary (induced) embryo
Neural tube
Notochord
Neural tube (mostly nonpigmented cells)
Figure 47.25
CONCLUSIONThe transplanted dorsal lip was able to induce cells in a different region of the recipient to form
structures different from their normal fate. In effect, the dorsal lip “organized” the later development of an entire embryo.
Indeterminant
cleavage
In molluscs and
annelids, the
first cleavage is
determinate,
separating vital
cytoplasmic
constituents
Formation of the Vertebrate
Limb
• Inductive signals play a major role in
pattern formation
– The development of an animal’s spatial
organization
• The molecular cues that control pattern
formation, called positional information
– Tell a cell where it is with respect to the
animal’s body axes
– Determine how the cell and its descendents
respond to future molecular signals
• The wings and legs of chicks, like all
vertebrate limbs
– Begin as bumps of tissue called limb buds
(a) Organizer regions. Vertebrate limbs develop from
protrusions called limb buds, each consisting of
mesoderm cells covered by a layer of ectoderm.
Two regions, termed the apical ectodermal ridge
(AER, shown in this SEM) and the zone of polarizing
activity (ZPA), play key organizer roles in limb
pattern formation.
Anterior
AER
Limb bud
ZPA
Posterior
Apical
ectodermal
ridge
Figure 47.26a
50 µm
• The embryonic cells within a limb bud
– Respond to positional information indicating
location along three axes
(b) Wing of chick embryo. As the bud develops into a
limb, a specific pattern of tissues emerges. In the
chick wing, for example, the three digits are always
present in the arrangement shown here. Pattern
formation requires each embryonic cell to receive
some kind of positional information indicating
location along the three axes of the limb. The AER
and ZPA secrete molecules that help provide this
information.
Figure 47.26b
Digits
Anterior
Ventral
Distal
Proximal
Dorsal
Posterior
Inductive
signals causes
pattern
formation
AER apical
ZPA
Positional
information in
the chick limb
bud responds to
molecular cues
from organizier
regions
• One limb-bud organizer region is the apical
ectodermal ridge (AER)
– A thickened area of ectoderm at the tip of the bud
• The second major limb-bud organizer region is
the zone of polarizing activity (ZPA)
– A block of mesodermal tissue located underneath the
ectoderm where the posterior side of the bud is
attached to the body
If AER is placed onto other
region that is almost
completed with
development
• Tissue transplantation experiments
– Support the hypothesis that the ZPA produces
some sort of inductive signal that conveys
positional information indicating “posterior”
EXPERIMENT ZPA tissue from a donor chick embryo was transplanted under the ectoderm in the
anterior margin of a recipient chick limb bud.
Anterior
Donor
limb
bud
New ZPA
Host
limb
bud
ZPA
Posterior
RESULTS
In the grafted host limb bud, extra digits developed from host tissue in a mirror-image
arrangement to the normal digits, which also formed (see Figure 47.26b for a diagram of a normal
chick wing).
Figure 47.27
CONCLUSION The mirror-image duplication observed in this experiment suggests that ZPA cells secrete
a signal that diffuses from its source and conveys positional information indicating “posterior.” As the
distance from the ZPA increases, the signal concentration decreases and hence more anterior digits develop.
ZPA
transplanted
ZPA zone of
polarizing activity
determines anteriorposterior axis
• Signal molecules produced by inducing
cells
– Influence gene expression in the cells that
receive them
– Lead to differentiation and the development of
particular structures
Doctors grow organs from
patients' own cells
Tuesday, April 4,
2006; Posted: 9:37
a.m. EDT (13:37 GMT)
Cells from a
patient's
bladder are
grown in a Petri
dish then
layered onto a
bladder-shaped
mold.
Humans Could Regenerate Tissue Like Newts Do By Switching Off
a Single Gene
By Clay Dillow Posted
03.16.2010
Regrowing Tissues Like Newts By shutting off a single gene,
researchers think humans could regenerate damaged tissue just as
newts do. J. Carmichael
Scientists have long been stymied by human regenerative healing - that is, wholesale regrowth of, say, a severed limb -- an ability
inherent in some species but lost on humans. But new research
suggests the ability to regenerate isn't based on something newts
and flatworms have that we don't; rather, it's something we do have
that's keeping us from regenerating tissues. Researchers think a
gene called p21 may control regenerative healing, and that by
switching it off, humans could perform our own regeneration.
The new research suggests that the potential to heal without
scarring -- or possibly even to regrow a limb, albeit in a limited
manner -- may lie dormant in human cells, kept in check by the p21
gene. A group of lab mice engineered to lack p21 were able to
regenerate surgically removed tissue to the point that no evidence
of the surgery remained. Holes punched in their ears -- a standard
procedure for tagging lab animals -- also healed perfectly, leaving
behind no traces of scar tissue or previous damage.
Essentially, switching off the p21 gene allows adult cells to behave like pluripotent stem cells, reorienting themselves into
whatever kind of tissue they need to be. But naturally there is a give-and-take; p21 is closely intertwined with another gene,
p53, a cell-division regulator that, if allowed to run amok, can lead to many types of cancers. The p21 gene acts as a safety
valve for p53, stopping cell division in the case of DNA damage. So switching off p21 can allow cells to engage in
regenerative healing, but the risks of doing so include rampant cell division (read: cancer).
However, in the p21-free lab mice there was no cancer surge as one might expect, but rather an increase in apoptosis, or cell
suicide, which directs damaged cells to destroy themselves. So it would appear that by striking some kind of controlled
balance between allowing regenerative cells to work, while letting apoptosis regulate out-of-control cell division, could lead
to regenerative treatments for humans somewhere down the road.