The formation of a complex multicellular organism from a single cell is one of the
most amazing processes of biology. Embryonic development is characterized by the careful
regulation of cellular behaviors such that cells proliferate, migrate, differentiate,
and form tissues at the correct place and time. These processes are genetically controlled
and depend both on the history of cells, their lineage, and on the activities of signaling
pathways, which coordinate the cell interactions leading to organogenesis.
A limited number of key signaling pathways—Fgf, Hedgehog, Wnt, TGFß, Notch among the
most important—operate during development, acting repeatedly at different times and
in different regions in the embryo and eliciting diverse cellular responses. This
raises the question of how cells integrate all the information they receive and can
respond in cell type-specific ways to the same signals. Classical concepts in embryology
such as organizers (groups of cells producing instructive signals) and competence
(ability of cells to respond) can now be analyzed in molecular terms. In recent years
many advances have been made in identifying the signals acting during embryo development
and understanding their properties and functions, which is equally of relevance for
human pathology and evolution. An important discovery is the conservation of signals
and mechanisms, not only in evolutionary terms (similar genes and signals acting in
distant organisms), but also in the repeated use of the same signaling pathways at
different times and places in the embryos. Moreover, many of those mechanisms are
involved in adult tissue homeostasis and regeneration.
Understanding developmental signaling pathways is important for several reasons. It
gives us information about basic mechanisms of cell function and interactions needed
for morphogenesis and organogenesis. It uncovers the basis of congenital malformations,
since errors at any step of cell signaling during development are a major cause of
defects. Fundamental insight also gives us clues to understand the mechanisms operating
in evolution that explain diversity in form and function. And finally, it allows the
identification of possible causes of disease in the adult organism (such as cancer
or degenerative diseases) pinpointing possible targets for therapeutic approaches.
In this context, the aim of the Frontiers research topic “Signaling pathways in embryonic
development” has been to provide a forum for experts in cell and developmental biology
to share recent advances in the field of signaling during embryonic development. Sixteen
articles in a variety of formats are united in this Topic, offering a valuable collection
for researchers looking for an update in the knowledge of signaling pathways operating
during embryogenesis. The works, focused mainly on vertebrates, explore different
aspects of this theme from cell communication to organ formation and have implications
for areas as distant as evolution or pathology.
Among the signaling pathways with important and widespread roles in development is
the Wnt pathway, comprising a family of ligands with homology to wingless in Drosophila.
Wnts can bind to multiple receptor complexes and trigger several downstream signaling
cascades [including the so-called canonical WNT/β-catenin dependent signaling pathway,
the non-canonical WNT/planar cell polarity (PCP), and the WNT/Ca2+ pathways], illustrating
how the same signal can elicit diverse cellular responses depending on the cell type,
context, and developmental timing. Fujimura reviews the role of canonical Wnt signaling
in eye development, highlighting the important roles it plays in patterning of ocular
tissue, differentiation of retinal pigment epithelium, and morphogenesis of the optic
cup. Importantly, mis-regulation of the signaling cascade can lead to eye malformations
and disease. Gentzel and Schambony review a group of core intracellular effectors
of the Wnt pathway, disheveled (DVL) proteins, which comprise three members in vertebrates.
Although all DVLs share a common basic function in Wnt signaling, the expression patterns,
and functions of the different isoforms are not totally redundant and have also diverged
between different species, suggesting they play specific roles depending on the tissue
distribution and specific interactions. Again, mutations in DVL genes can cause human
congenital disease, highlighting their important role in development. Additionally,
Berger et al. review the role of PTK7 (protein tyrosine kinase 7, a transmembrane
receptor) in the fine-tuning of the Wnt signaling network. Its functions in establishing
cell polarity, regulation of cell movements, and migration are also essential for
development and disease, particularly in cancer and metastasis.
Another important signaling pathway is Notch, a transmembrane protein that mediates
juxtacrine cell-cell communication. Notch has many functions in organ formation and
adult homeostasis, including cell determination and stem cell maintenance. Carrieri
and Dale review the particularly well-studied function of Notch in somitogenesis and
also present recent data on the role of FBXW7 protein in regulating the turnover of
Notch intracellular domain (NICD, the effector of the pathway), in development and
cancer. This relates to an often-overlooked essential point in signaling, which is
the termination of activation and resetting of the components, allowing the cells
to become competent again. Multiple mechanisms of regulation exist (positive and negative
feedback loops) that allow a fine control of signaling pathways at different steps
of the intracellular cascades.
Crosstalk between the limited numbers of signaling pathways is a mechanism that allows
cells to respond differently to the same signal, producing the diverse cellular behaviors
that are needed to build tissues and organs. A new example of this is provided by
Bernatik et al. reporting on the role of the BMP antagonist Noggin in sensitizing
cells and potentiating the activation of non-canonical Wnt signaling in skeletal development.
They also provide evidence for a genetic interaction between these two pathways, which
are involved in human congenital malformations.
The role of specific signaling pathways in the formation of particular organs is discussed
in other articles. Díez del Corral and Morales review the multiple roles of Fgf signaling
in the developing spinal cord. This important structure of the nervous system arises
from neural derivatives of an early neuromesodermal population located at the caudal
part of the embryo. Extension of this region is coupled to spinal cord formation and
several essential processes such as neurogenesis, ventral patterning or neural crest
specification are controlled by Fgf signaling. These embryonic functions of Fgfs could
be related to its ability to promote regeneration in the injured spinal cord of adults.
Signalling pathways often converge on controlling the expression of transcription
factors, which regulate cell fate specification. The integration of Notch signaling
and bHLH transcription factors during inner ear development is analyzed by Gálvez
et al. which also highlight that these same mechanisms are involved in hair cell regeneration,
opening avenues for possible therapeutic approaches in hearing impairment. Ear development
is also the topic reviewed by Magariños et al. They present evidence for a crucial
role of autophagy, the regulated process of degradation, and recycling of cellular
components, in vertebrate inner ear formation.
The limb is a classic model in embryology and some of the most important discoveries
related to the roles of signaling pathways in pattern formation, growth, and differentiation
have been made studying limb development. Tickle and Towers review the role of Shh
in this process, a paradigm of how signals control and integrate tissue pattern and
growth. They also discuss the implications of this important pathway for congenital
malformations in humans and for the generation of limb morphological diversity during
evolution. Montero et al. also treat this evolutionary aspect in their perspective
article. They present a detailed analysis of Sox9 expression in developing digits
of several species. This transcription factor, regulated by signaling pathways such
as BMPs, Tgfßs, or Fgfs is involved in formation of the chondrogenic template of the
skeleton. Differences in Sox9 expression patterns among species that have specific
morphologies may reflect differences in signaling pathways controlling its expression.
Also related to skeletal development, Amara et al. show that the effects of Calcium/Calmodulin
dependent kinase II (CAMKII), an effector for Ca+2 -dependent signal transduction,
in promoting chondrogenic differentiation seems to be specific for chicken embryos.
This function is not observed in the mouse, thus highlighting the existence of differences
in signaling functions and regulation among different species.
Integration of extrinsic and intrinsic regulatory cues is essential for organ formation.
Dueñas et al. review the role of signals, transcription factors and cellular processes
in the formation of the epicardium. This is the external-most layer of the heart that
serves not only as the outer cover for this organ, but also seems to play a role in
regeneration. Thus, understanding the basis of its development may have important
therapeutic implications. Two articles deal with muscle development. Hernandez-Torres
et al. review the role of Pitx2 in embryonic and adult myogenesis. A hierarchy of
transcription factors controls skeletal muscle differentiation and Pitx2 plays an
important role in the regulation of this process. Importantly, it also seems to be
involved in the establishment and function of satellite cells, the stem cells resident
in adult muscle, thus opening new avenues for development of regenerative therapies.
Additionally, Nassari et al. review the role of connective tissues in muscle development.
Apart from the intrinsic molecular signals mentioned above, the interaction of muscle
cells with surrounding tissues (bone, cartilage, tendon, and ligament) is critical
for the correct assembly of the musculoskeletal system during development and for
maintaining adult homeostasis.
An emerging theme in developmental biology is the control of tissue morphogenesis
by physical forces (mechanotransduction). Valdivia et al. review the mechanical control
of myotendinous junction formation and tendon differentiation, highlighting again
the importance of the interplay between chemical and mechanical signaling during embryogenesis.
In the same line, Stricker et al. provide a timely discussion reminding us that cells
in embryos and adult organisms are not present in isolation, but embedded in extracellular
matrices into complex tissues. Cells attach to the ECM and sense its mechanical properties.
Typically, experimental in vitro conditions do not fully reproduce this environment,
which is however critical for the physiological cellular responses to signaling cascades.
The challenge for the future is to try and integrate as many interactions as possible
when designing experiments.
We hope that the articles in this topic will be of interest to researchers working
in development and cell biology, fuelling discussion on this area and opening new
avenues for thinking and investigation.
JS was the Guest editor of this Research Topic, inviting co-editors AM and SS and
working with them to define the subjects to be treated. They identified and invited
leaders in specific research fields to contribute their work to the Research Topic.
They acted as handling editors of manuscripts in the topic. JS wrote the Editorial
with input from the other co-editors.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.