Amanda important developmental steps during early embryogenesis is

Amanda
Linke

Biol211
Essay Prompt: Discuss the importance of intercellular signaling in development.

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Role of Intercellular Signaling
During Embryogenesis

The information needed to
create a fully developed organism is stored within all cells, but during
development this information must be correctly translated and interpreted.
Cells are constantly signaling each other during development through secreted
signals, communicating important information which allows cells to establish
body axes, layout a body plan, and differentiate in order to properly form the
embryo. Mutation or misinterpretation of these signals translates into
developmental abnormalities which may kill the embryo or lead to phenotypic
malformations. The correct use
and interpretation of intercellular signaling is therefore essential for the
correct formation of the embryo during development. TRD1 

Body
axes establishment

One
of the first and most important developmental steps during early embryogenesis
is the process of gastrulation, which differentiates ofTRD2 
the fertilized oocyte into the ectoderm, mesoderm, and endoderm germ layers.
Fibroblast Growth Factor (FGF) signaling plays a central role in gastrulation
and helps establish the dorsal/ventral and left/right axes of the developing
embryo by specifying mesodermal cell fates through the Ras/MAPK cascade (Oki et
al, 2010). This
step establishes the first oriental axes in the developing embryo and organizes
the rest of the organism to form properly around these axes, making it a
crucial developmental step towards the correct differentiation and growth of
the embryo. TRD3 

Mutations
of the FGF signaling pathway can cause major embryonic abnormalities and can
interfere with or arrest proper development. For example, in mouse embryos
growth factor FGF8 and its receptor FGF1 have important roles in gastrulation
and formation of left/right axes. ItTRD4 
induces Snail expression, which
downregulates ectodermal genes in the mesoderm by repressing E-cadherin, and induces TRD5 T and Tbx6 expression which specifies mesodermal fate and helps establish
the left/right axis via Notch signaling. In FGF8 negative mouse embryos, however,
epiblast cells are able to move the TRD6 primitive
streak and undergo the epithelial-to-mesenchymal transition (EMT) but are
unable to move away from the streak, preventing mesodermal and endodermal
tissues from forming and greatly mutating the developing embryo (Sun et al,
1999). The lack of intercellular FGF signaling causes EMT and mesodermal
patterning defects,
greatly mutating the embryo and preventing it from properly developing. TRD7 

The
Wnt signaling pathway is also crucial for establishing body axes, most notably
in the form of the dorsal/ventral axis by creating the Spemann organizer from
the Nieuwkoop center, establishing the dorsal side of the embryo (Amerongen and
Nusse). The Spemann organizer instigates development of the central nervous system
by inducing
cells into becoming neural TRD8 plate
cells, which will fold together to form the neural tube and eventually the
spinal chord, forbrain, midbrain, and hindbrain. The Spemann organizer also
establishes the anterior/posterior axis in the neural tube via Wnt and BMP
signaling. For
example, the Spemann organizer secretes Cerebus and insulin-like growth factors
which inhibits Wnt and BMP signals in order to form the head region, while the
posterior region is established by a Wnt and BMP signal gradient (Neurulation
and the Notochord, 2010). TRD9 

Body
plan establishment

After
the body axes have been established cells can begin to transmit information
about the body plan of the organism. TRD10 The
Hedgehog (hh) signaling pathway is one of the key methods by which this occurs.
TRD11 In
the Hedgehog signaling pathway the hh TRD12 protein
is produced and processed in the cytoplasm, creating an active protein and two
lipids, which help transport and attach the protein to the cell membrane. The
cell can then generate a protein gradient in the extracellular space so that
other cells can respond to the proteins through Patched (Ptch), a transmembrane
receptor protein. When Ptch is inactive it inhibits Smoothened (Smo), another
transmembrane protein which inhibits the transcription of certain genes. Ptch
becomes activated upon hh ligand binding, activating the Smo protein and
causing an hh signal cascade which finally initiates transcription of specific
genes (Mohler, 1998?). TRD13 

Mutations
or abnormalities in the hh signaling pathway cause major phenotypic changes;
for example, in some hh mutant drosophila the embryo will grow to be short and
stubby compared to wild type embryos, and can grow “lawns” of denticles instead
of rows, making the embryo look short and hairy like its namesake (Mohler, 1988).
TRD14 Mutations
in hh signaling are typically embryonic lethal, demonstrating the clear
importance of efficient intercellular signaling in development. TRD15 

Intercellular
signaling plays a crucial role in both body axis formation and body plan
initiation. Mutations of FGF or Wnt signaling, which both contribute to body
axis formation, prevent normal development and lead to extreme phenotypic
abnormalities or embryonic termination. Mutations of hh genes, which establishes TRD16 embryonic
body segments, also causes TRD17 extreme
phenotypic irregularities. Successful embryonic development depends on the
accurate intercellular signaling which determines cell fates.

Differentiation

While
the body axes and body plan are being established cells can begin to
differentiate within their germ layers via induction, the process by which
cells determine other cell’s fates through intercellular signaling. There are 6
major signaling pathways by which differentiation occurs: FGF, SHH, BMP, Notch,
canonical Wnt, and noncanonical Wnt. TRD18 Each
signaling pathway influences the differentiation of embryonic stem cells into
particular tissues depending on its location according to the established body
plan. However, an embryo can only successfully develop when these signaling
pathways are used appropriately and interpreted correctly.

Notch
signaling allows for differentiation between adjacent cells via lateral
inhibition giving rise to asymmetric cell division, whereby one daughter cell
has a different cell fate than the original cell. Initially cells in a cluster
express both Delta and Notch, but a random change in gene expression changes
the balance of ligands and receptors on a cell such that a cell expresses more
Delta. The asymmetry is generated when the cell can stably express Delta,
becoming the signal sender and activating Notch signaling so that the adjacent
cells can adopt their cell fates (Perrimon, 2001). Notch signaling is activated
when the Notch receptor extracellular domain binds to Delta and DSL ligands on
an adjacent cell, inducing a conformational change in Notch, exposing an
ADAM10/TACE cleavage site. This site is cleaved by y-secretase, releasing the
Notch intracellular domain (NICD) which then travels to the nucleus and
complexes with coactivators (CoA) and Mastermind (Mam) to replace corepressors
(CoR) which occupy CLS bound Notch target gene promoters like Hes genes. Hes
inhibits expression of genes like Mash1, whereas cells which do not receive
Notch signals express Mash1, upregulating expression of Notch ligand DSL
(Brasson, 2012).  TRD19 

Mutations
in the Notch signaling pathway can affect cell fate decisions and prevent cells
from properly differentiating. For example, the Notch signaling pathway plays a
large part in differentiating cells in the gut of Zebrafish. In Zebrafish with
a defective Delta ligand Notch signaling was unable to take place and the
epithelial cells defaulted into secretory cells, overproducing secretory cells
and producing no absorptive cells (Crosnier et al, 2005). This shows TRD20 that
the Notch pathway is crucial to the correct differentiation between adjacent
tissues and that mutations in this type of intercellular signaling causes
extreme developmental problems.

Development
of complex structures like limbs require much intercellular signaling. TRD21 Stimulation
of limb bud development is caused by expression of Tbx5 in the forelimb and
Tbx4 in the hindlimb. Both T-box transcription factors stimulate the expression
of FGF10 by the mesodermal cells, which in turn stimulates the ectodermal cells
to produce FGF8, establishing a feedback loop which initiates limb development
(Zuniga, 2015). The correct expression of Tbx5, and consequentially FGF10
signal pathway, is crucial to proper limb development. For example, in FGF10
knockout mice the limbs and lungs fail to form, while if a bead soaked in FGF10
is implanted into a mouse embryo an extra limb will develop at that spot.

The
birth defect Amelia is also an outcome of mutations in FGF signaling, resulting
in the underdevelopment or lack of one or more limbs (Limb Development, 2015). Brachydactyly,
an inherited human hand malformation syndrome causing shortness in the fingers,
is another defect caused by mutations of intercellular signaling. However,
brachydactyly is caused by mutations of BMP signaling pathways resulting in the
failure to receive or misinterpretation of the signals (Bernatik, 2017). Mutations
in intercellular signaling pathways such as the FGF or BMP pathway can result
in huge phenotypic abnormalities which, if not embryonic lethal, could greatly
impair the developing organism and prevent it from growing and developing
normally.

Cell
signaling is responsible for the differentiation of cells so that limbs and organs
can properly develop. FGF, Notch, and BMP are among the most prevalent
intercellular signaling pathways and facilitate the correct development of the
embryo when used and interpreted accurately. However, mutations of these
signaling pathways can lead to drastic phenotypic changes like the Amelia birth
defect or Brachydactyly syndrome, which can greatly impair the organism and
prevent it from living normally.

Conclusion: 

Embryogenesis
is a complex process which depends on intercellular signaling to convey body
axes, establish a body plan, and differentiate cells so that they can begin to
develop the limbs and organs necessary for normal development. TRD22 Signaling
pathways such as Notch, BMP, FGF, SHH, and Wnt play a crucial role in conveying
this information, while mutations of these pathways can be embryonic lethal or
inflict debilitating defects on the organism. Development depends on the
accurate transmission and interpretation of intercellular signals, without
which embryogenesis would be impossible to complete.

 

 

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