Tatum signalling cascade that leads to the downstream

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Tatum Dam

BIO211- Cell Biology

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

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Total Word Count: 1702

Essay Word Count: 1492


Why is intercellular signalling important in development?

The differentiation and regulation of
developing cells is controlled through a remarkably small number of signalling
pathways. Within these pathways, the propagation of intercellular signals
results in the transcription of target genes that specify cell fate. These
signals are necessary for the development of an undifferentiated stem cell into
its specialized type, which determines the structure and refinement of future body
parts. Malfunctions during intercellular signalling are associated with issues during
embryonic development and many diseases (Dennis and Bradshaw, 2011). In this
essay, the effects of cell fate specification within three intercellular signalling
pathways – TGF-?, Sonic hedgehog, and Notch – will be investigated.
First, the relationship between TGF-?
signalling and gastrulation will be explored. Second, the function of Sonic
hedgehog signalling within the induction of the chick limb bud will be
examined. Third, the way in which Notch signalling creates the adult lung will
be scrutinized. Fourth, the harmful effects of dysregulation during intercellular
signalling will be considered as well as possible methods for new drug therapy.
Overall, intercellular signalling plays a fundamental role in controlling cell
fate specification; alterations within the process can hinder survival by creating
defects within embryos and life-threatening diseases. Additionally, greater
understanding of how intercellular signalling is affected by mutations will be
key for creating future drug therapies.

Firstly, the transduction
of the TGF-? signalling pathway is essential for embryonic development –
specifically the induction of the endoderm, mesoderm, and ectoderm layers of
vertebrates. When turned on, TGF-? receptors activate a signalling cascade that
leads to the downstream activation of substrates and regulatory proteins specifying
cell fate (Park, 2011). The varying levels of Nodal signalling in different
areas of the embryo define their patterning and refinement. For instance, nodal
ligands and nodal-related Vg1 are highly concentrated in the dorsal vegetal
region of Xenopus, fading ventrally. In zebrafish, there is a similar gradient
where a higher concentration of nodal-related genes Squint (Sqt) exists on the
dorsal side of the embryo (Massagué,
2012). These nodal gradients are vital for the
induction of the endoderm and mesoderm layer. The third germ layer, ectoderm,
is formed in the embryo when Nodal signalling is inhibited (Gilbert 2000). TGF-? signalling therefore plays a direct role in the
induction of the endoderm and mesoderm layers, while indirectly affecting the
cell fate specification of the ectoderm layer. Expectedly, organisms with
errors in this signalling process experience mutated phenotypes. For instance,
fish with mutations in short and long range nodal related ligands, Cyclops (Cyc) and Squint (Sqt), have almost
no mesoderm and are completely absent of endoderm (Massagué, 2012). Overall, the activation and deactivation of TGF-? signalling controls the nodal gradient that define the
endoderm, mesoderm, and, indirectly, ectoderm layers; without this process
embryonic gastrulation is at risk.                         

The second
intercellular signalling pathway vital for embryonic development is the Sonic
hedgehog signalling (Shh) pathway, which uses long range signalling in order to
induce positional values across the chick limb bud (Tickle and Towers, 2017).
When Sonic hedgehog is present, an intercellular signal is propagated that
eventually results in the dissociation of a complex and release of Cubitus
Interruptus (Ci). Cubitus Interruptus then moves to the nucleus in order to
turn on target genes (Abidi, 2014). Sonic hedgehog signalling is activated
within the polarizing region of the chick, where the Sonic hedgehog protein is
believed to have morphogenic properties that specify positional values across
the antero-posterior axis of the limb. By inducing the proliferation of
mesenchyme cells and regulating the anteroposterior length of the apical
ectodermal ridge, the Sonic hedgehog signalling pathway is able to control the
width of the limb bud (Tickle and Towers, 2017).                                             

In order to examine the
relationship between Sonic hedgehog signalling and chick development,
scientists grafted the polarizing region to the anterior margin of another wing
bud. The experiment proved how the Sonic hedgehog signalling pathway specified positional
values in chick limb buds, as seen in Figure 1 (Tickle and Towers, 2017).

The figure showcases the mirror image of the positional values of the graft and
host, which each specify 3 digits. The polarizing region, containing Sonic
hedgehog genes, was grafted to the anterior margin of another wing bud. The
Sonic hedgehog gradient specified the antero-posterior positional values for
the three digits formed next to cells made from the polarizing region. The
result is six digits patterned 3-2-1-1-2-3 from anterior to posterior, created
by the grafted polarizing region (Tickle
and Towers, 2017).


By examining the relationship
between Sonic hedgehog signalling and the chick limb bud, scientists were able
to make a number of discoveries as to how digits are specified and mutated. During
this experiment, scientists discovered the highest threshold concentration in
the tissue closest to the polarizing region, which specified the most posterior
digit (Digit 3). Meanwhile, the tissue with the lowest threshold concentration
existed in the tissue farthest away from the most anterior digit (Digit 1). Additionally,
further testing showed that inactivity in Gli genes resulted in polydactylous
or morphologically similar digits within chick limb bud (Tickle and Towers,
2017). These experiments demonstrate that the identity of digits within the
chick limb bud is determined by the threshold concentration possessed at the positional
value and alterations during Sonic hedgehog signalling is implicated in limb
defects. Without the ability to use long-range Sonic hedgehog signalling to
specify positional values across the antero-posterior axis, proper formation of
the chick limb bud would not occur.

Lastly, the third intercellular signalling
pathway necessary for embryonic development is the Notch signalling pathway, which
is responsible for the induction of the adult lung. When the Notch ligand is activated, repressor
proteins are released from the CSL complex, allowing for the expression of
target genes (Okajima, 2018). The result of this is the differentiation of
basal cells, creating the pseudostratified
airway epithelial in the developing and adult lung. Basal cells express Jag
ligands under homeostatic conditions but do not activate Notch signalling until
a population of p63+ basal cells is fully grown. Notch3 is then selectively
expressed in cells in the parabasal position, where adjacent basal cells use Jag1
and Jag2 to activate additional Notch3 signalling. These p63+ basal cells will
remain unspecified until Notch1 and Notch2 signalling is turned on for the
differentiation of secretory multiciliated cells, as shown in Figure 2 (Mori
et. al, 2015).


Figure 2: Within this air liquid interface culture, Notch3 is
selectively activated in cells occupying the parabasal position. On Day 0,
there are clear nuclear signals for Notch3, but signals for Notch1 and Notch2
do not occur until later in differentiation (Mori
et. al, 2015).


Disruptions in this mechanism will cause
expansion in basal cells and altered pseudo stratification, showcasing the
necessity of Notch signaling in lung development (Mori et. al, 2015). Since
Notch signaling has a vital role in the differentiation of basal cells,
research in this process may lead to discoveries related to pathogenesis in the



Many diseases are correlated to
mutations in these intercellular signallling pathways, due to dysregulations
during cell fate specification (Dennis and Bradshaw, 2011). For instance,
certain basal cell carcinomas are linked to autonomous activation of hedgehog
signaling in the absence of a ligand due to a mutation in PTCH1 that prevents
it from binding to SMO, shown in Figure 3 and 4 (Crowson, 2006).  

3: A
mutation in PTCH1 causes the protein to become truncated, preventing it from
binding to and repressing Smoothened (SMO) in the phospholipid bilayer of the
plasma membrane. Since SMO no longer requires the presence of a Sonic hedgehog
ligand to inhibit PTCH1, constitutive upregulation of SMO expression occurs (Crowson, 2006). 


Figure 4: When SMO is freed, it is able to act as a signal
transducer that upregulates expression of Gli-1 and Gli-2 proteins, glioblastoma
signalling proteins (Crowson, 2006).   Activation of Gli-1 and Gli-2 helps mediate
aberrant hedgehog signalling in the nucleus of epidermal cells and induces
oncogenic transcription (Gilbert, 2000).


Abnormal activation of the Sonic
hedgehog pathway transforms adult stem cells into cancer cells that induce
tumorigenesis, demonstrating the importance of regulation during cell fate
specification (Crowson, 2006). However, combatting mutations that stem from
intercellular signalling can be incredibly difficult. For example, one way of
treating basal cell carcinoma is by targeting SMO with inhibitors. This however
puts the transduction of other signalling pathways at risk since SMO can be
independently activated. Additionally, clinical trials prove that increasing
drug resistance decrease the efficacy of SMO inhibitors. This leads to the question:
how do scientists create drug treatments effective enough to overcome drug
resistance without threatening to disrupt the transduction of important
downstream targets?

Dysregulations in intercellular signalling
threaten proper cellular development, however creating innovative drug
therapies may solve this. First off, drugs should be designed to fit the need
of each tumor model in order to minimize dangerous side effects. For instance,
patients suffering from ligand independent signalling should receive Sonic hedgehog
inhibitors that act at the level of SMO and not the full extent of PTCH1, since
these cancers are associated with a ligand independent pathway (Abidi, 2014).
Secondly, drugs should be developed in order to target multiple sites,
including sites that may cause drug resistance. For example, the inhibitor
MRT-92 has already been proven effective in treating medulloblastoma patients
by binding onto multiple sites of SMO and attacking the SMO D473H mutant, which
is known for partially blocking drug entry (Rimkus,
Carpenter, Qasem, Chan, and Lo, 2016). By creating inhibitors that are specific
yet combat multiple mutant sites, scientists may be able to combat aberrant
cell fate specializations that stem from disruptions in intercellular signalling.

In total, the development of a stem cell
into its fully functioning cell type is regulated through intercellular signalling,
a crucial process that determines the strength, functionality, and appearance
of an organism’s body. The propagation of an intercellular signal allows for
the eventual transcription of target genes that induce cellular
differentiation. This process is particularly important for the refinement and
patterning of organisms during embryonic development (Basson, 2012). From
inducing the primary germ layers in TGF-? signalling, creating the adult lung
in Notch signalling, and specifying the positional values of chick limb buds,
intercellular signalling plays an incredibly diverse role in determining cell
fate. Alterations within intercellular signalling can result in organisms with
mutated phenotypes as well as life-threatening illnesses, due to issues with proper
cell fate specification (Crowson, 2006). However, by developing new drug
therapies, such as inhibitors that target multiple sites without hindering the
transduction of other downstream targets, scientists may be able to combat the
dysregulations that threaten the development of stem cells (Rimkus, Carpenter, Qasem, Chan, and Lo, 2016). Due to the
essential role of intercellular signalling within the activation of target
genes that regulate cellular differentiation, it is critical to protect this pathway
from mutations that give rise to embryonic defects and fatal diseases.





Abidi, A. (2014). Hedgehog
signaling pathway: A novel target for cancer therapy: Vismodegib, a promising
therapeutic option in treatment of basal cell carcinomas. Indian Journal of
Pharmacology, 46(1), 3–12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3912804/

Basson, M. A. (2012) Signaling in Cell Differentiation and
Morphogenesis. Cold
Spring Harbor Perspectives in Biology, 4(6), a008151.

3.     Crowson, A. Neil (2006) Basal cell carcinoma:
biology, morphology and clinical implications, Nature Modern Pathology, https://www.nature.com/articles/3800512.

4.     Dennis, E. & Bradshaw, R. (2011)
Intercellular Signalling in Development and Disease (1st Edition),
Academic Press, Massachusetts.

5.     Gilbert S.F. (2003) Developmental
Biology (7th Edition) Sunderland: Sinauer Associates, Massachusetts.

6.     Massagué, Joan (2012) TGF? signalling
in context. Nature Reviews Molecular Cell Biology,  https://www.nature.com/articles/nrm3434.

7.     Mori, M., Mahoney, J.
E., Stupnikov, M. R., Paez-Cortez, J. R., Szymaniak, A. D., Varelas, X.,
Cardoso, W. V. (2015) Notch3-Jagged signaling controls the pool of
undifferentiated airway progenitors. Development (Cambridge, England), 142(2), 258–267. https://www.ncbi.nlm.nih.gov/pubmed/25564622

8.     Park, K.-S. (2011)
TGF-beta Family Signaling in Embryonic Stem Cells. International Journal of Stem Cells, 4(1), 18–23.

9.     Okajima, Tetsuya (2018) Notch
Signalling: A sweet strategy. Nature Chemical Biology, https://www.nature.com/articles/nchembio.2532


Rimkus, T. K., Carpenter, R.
L., Qasem, S., Chan, M., & Lo, H.-W. (2016). Targeting the Sonic Hedgehog
Signaling Pathway: Review of Smoothened and GLI Inhibitors. Cancers, 8(2), 22.

11.  Tickle, C., &
Towers, M. (2017). Sonic Hedgehog Signaling in Limb Development. Frontiers in Cell and Developmental
Biology, https://www.frontiersin.org/articles/10.3389/fcell.2017.00014/full





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