Cell Differentiation: Cell
interactions in Development
Patricia Zuk, PhD
Research Director
Regenerative Biogengineering and Repair (REBAR) Lab
Department of Surgery
David Geffen School of Medicine at UCLA
• so cells can interact with each other and
with their environment
• this interaction turns specific signaling
paths ON or OFF
• these pathways become important for
mediating proliferation, differentiation and
apoptosis
• all three are crucial to development
Differentiation: Stem
cells
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so fertilization of the egg
takes place in the oviduct
the fertilizes zygote travels
to the uterus for implantation
along the way – the zygote
begins to divide (mitosis)
2-cell, 4-cell, 8-cell
embryonic stages etc….
the embryo reaches a stage
called the morula = ball of
small cells (embryo has not
enlargened)
by the end of the first week
the second embryonic stage
– the blastocyst - forms
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Differentiation: Embryonic Stem
cells
the blastocyst is a hollow
ball of cells containing an
outer rings of progenitor
cells = trophoblast and an
inner mass of cells at one
end of the embryo = inner
cell mass
it is these ICM cells that are
the source for the
derivation of embryonic
stem (ES) cells
the ES cells are said to be totipotent – have the ability to specialize or differentiate
into ALL cells of the embryo
the blastocyst then begins a process of differentiation and these ES cells form
populations of stem cells with more restricted potentials
the ES cells first differentiate into two layers called the embryonic disc – divides the
blastocyst cavity into an amniotic cavity and a yolk sac (primitive hematopoietic
organ)
these two layers then continue to differentiate into the three germ layers of the
embyro
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ectoderm, mesoderm and endoderm
the formation of these germ layers marks the gastrula embryonic stage
Germ Layers
• the ectoderm, mesoderm and endoderm are thought to
be made up of stem cells with a more restricted
phenotype when compared to ES cells BUT still capable
of forming multiple cell types within that lineage
– e.g. pluripotent stem cells
• interactions between signaling molecules produced by
these germ layers and with the developing ECM around
these tissues results in specific developmental events =
patterning
• patterning requires the exposure of cells to a succession
of signals and subsequent activation of their associated
pathways
Cellular interactions in
development: Induction
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interactions between the cells of the germ
layers influence the fate of the stem cells
within these layers
can affect their differentiation paths
induction = mechanism where one cell
population influences the development of
neighbouring cells
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e.g. mesoderm induces the overlying
ectoderm to form neural tissue
embryonic development is a series of
inductive events
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binary – have a choice between one fate
or another (presence of one signal –
development down one path, absence of
signal – development down another path
gradient – multiple fates may result –
dependent upon the level or threshold of
the signaling molecule (these signaling
molecules are called morphogens)
relay – a signal induces a cascade which
determines the fate of cells in proximity –
these cells than produce additional signals
which affect the fate of their neighbours
Cellular Interactions: Patterning and TGFb superfamily
signaling
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a number of extracellular signaling molecules play roles in determining the fates
of developing cells and where these cells will develop
TGFb superfamily: TGFb, BMPs, activin (BMP2 and BMP4)
– wide role in development
– mediate proliferation of stem cells
– can determine stem cell fate – e.g. BMP4 = mesoderm
– also mediate the production of CAMs, growth factors, ECM molecules – all
which play roles in cell signaling and resulting differentiation responses
homologs found in multiple vertebrates
binding of these homologs to their receptors results in their activation
– this activation phosphorylates/activates downstream adaptors called Smads
– a cascade of Smads are activated resulting in eventual nuclear
translocation and regulation of gene expression
– these Smads are specific to the TGFb superfamily growth factor (Smad 1 =
BMP2, Smad 2 = TGFb)
– this signaling path is fine-tuned by the action of several adaptor proteins
(chordin, xolloid, noggin)
– this fine tuning can result in the induction of neural tissue as opposed
to mesodermal tissue and results in the patterning of tissues within
the embryo
Other Patterning Signal Paths
• numerous other patterning pathways comprised
of multiple signaling proteins
– e.g. hedgehog pathway – patterning of local tissues
and determination of cell fates
• initial studies in Drosophila
• homologs now characterized in vertebrates
• hedgehog (sonic and indian hh in vertebrates), wingless (Wnt
in vertebrates), patched, smoothened, dishevelled
• limb patterning – FGF, sonic hedghog,
• neural tube differentiation – sonic hedgehog gradients
Want to know how ridiculous this
gets??
• other signaling molecules in cell
differentiation/tissue fate determination
– brachyury – mesoderm
– goosecoid
– toll, spaetzle, cactus & dorsal
– dorsal targets: snail, twist, rhomboid
– delta, notch, jagged, suppressor of hairless
– hunchback, Kruppel
– even-skipped, fushi-tarazu