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The essential signaling pathways for animal development

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The  essential signaling pathways   for animal development 1

Signalling pathways are essential for multicellular development 

The emergence of multicellularity was supposedly, a major evolutionary leap. Indeed, most biologists consider it one of the most significant transitions in the evolutionary history of Earth’s inhabitants. “How a single cell made the leap to a complex organism is however one of life’s great mysteries. 

One of the far fetched and desperate pseudo-scientific attempts to explain how multicellularity emerged, can be read here.

Cell signaling is arguably the most important characteristic of multicellular organisms. 31 Without cell signaling, the different cells in the body of a plant or animal could not communicate with each other, and they could not coordinate their actions. Such coordination is essential: first, to build a complex body composed of thousands or millions of cells and second, for the correct performance of such a body in everyday life, whether acquiring nutrients, excreting toxins, or dealing with hostile or friendly interactions from other organisms. This coordination is corroborated by the many problems and diseases (such as developmental abnormalities and cancers) that arise from malfunction of the cellular machinery that deals with cell signaling and communication (13). Thus, the study of such cell signaling machinery is receiving a great deal of attention by biological and medical research. At the most basic level, any cell signaling process must involve a signal, synthesized or otherwise, generated by the sending cell and some kind of system to receive that signal and respond to it in the receiving cell. 

Less attention than this issue deserves,  has been given in the evolution/ID debate to elucidate  how cell signal transduction pathways function, what mechanisms, kind of molecules and proteins  are involved,, in what organisms they first emerged, and how these extremely complex and multifaceted  pathways could have possibly emerged, and what causes explain best their origins.  

Perhaps most surprising has been the finding that carbohydrates are also involved in the regulation of a number of signaling pathways. Genetic studies have  shown that proteoglycans/glycosaminylglycans play key roles in development, and, in Drosophila and Caenorhabditis elegans, they have been shown to be involved in regulating the fibroblast growth factor, Wnt, transforming growth factor-B, and Hedgehog signaling pathways. In vivo, oligosaccharides are synthesized by glycosyltransferases, each of which typically has a unique donor, acceptor, and linkage specificity. As such, a very large number of glycosyltransferases and related enzymes are required to generate the oligosaccharide diversity seen in nature. Although the basis for this diversity is not fully understood, general themes are beginning to emerge. The so-called terminal elaborations (e.g., sialic acid, galactose, and sulfate) typical of the N-linked oligosaccharides of multicellular organisms, for example, seem to have appeared as part of the machinery required to mediate cell–cell and cell–matrix interactions. 

Looking at how these pathways emerged might provide insights into how a few signalling pathways can generate so much cellular and morphological diversity during the development of individual organisms and the evolution of animal body plans.

If macroevolution involves changing morphological features, then the altering of signal transduction pathways becomes critical for any discussion of large scale evolution. 

Signalling pathways are  complex networks of interactions. Surprisingly, only a few classes of signalling pathways are sufficient to pattern a wide variety of cells, tissues and morphologies. The specificity of these pathways is based on the history of the cell (referred to as the ‘cell’s competence’), the intensity of the signal and the cross-regulatory interactions with other signalling cascades.

The origin,  formation and maintenance of  specialized tissues of multicellular organisms depend on the 

1. Coordinated regulation of cell size and number 
2. Cell morphology and shape
3. Cell location and migration 
4. Regulation and expression of differentiated functions

1. Coordinated regulation of cell size and number 
In the adult, homeostatic mechanisms maintain cell number and size to preserve organ size and function. However, this outward appearance of stability belies the complex balance of positive and negative regulatory stimuli required to maintain tissues with the differing proliferative and metabolic activities that make up a complex organism. 12 . In multicellular organisms, growth, proliferation, and survival need to be differentially regulated in different tissues, so additional levels of control are required. This is achieved by providing a more or less constant supply of nutrients systemically (by the bloodstream or its equivalent), but in addition, there is a requirement by each cell for an instructive signal to grow, proliferate, and survive. Thus, a combination of multiple growth, mitogenic, and survival signals with cell-specific responses provides the diverse signaling required to produce and maintain a complex adult organism.

Studies showing that cells require extracellular instructive signals to grow, coupled with the identification of key signaling pathways, have provided tractable systems for studying how cell growth is regulated. Moreover, the identification of abnormalities in these pathways in diseases as diverse as cancer, cardiac hypertrophy and neurodevelopmental disorders have highlighted the critical importance of the tight regulation of these pathways and have identified potential new therapeutic strategies.

The size of an adult organism is determined by both intrinsic developmental programs and by extracellular signals, which integrate to control cell number and cell size. 
Moreover, the water content of the cell must be controlled, requiring stringent controls of osmotic pressure (Koivusalo et al., 2009).
The Hippo pathway is also important in the control of tissue/organ size, mainly by regulating proliferation and apoptosis and thereby cell number (Tumaneng et al., 2012a). 

http://reasonandscience.heavenforum.org/t2350-the-hippo-signaling-pathway-in-organ-size-control-tissue-regeneration-and-stem-cell-self-renewal


2. Cell morphology and shape
depends on: 
(a) membrane targets and patterns 
(b) cytoskeletal arrays

(c) centrosomes 
(d) ion channels, and 
(e) sugar molecules on the exterior of cells (the sugar code)

(f)  Gene regulatory networks  19

3. Cell location and migration
Cell migration is a central process in the development and maintenance of multicellular organisms. 15 Processes such as tissue formation during embryonic development, wound healing, and immune responses, all require the orchestrated movement of cells in particular directions to specific locations. Errors during this process have serious consequences, including intellectual disability, vascular disease, tumor formation and metastasis. An understanding of the mechanism by which cells migrate may lead to the development of novel therapeutic strategies for controlling, for example, invasive tumor cells.

Cells often migrate in response to specific external signals, including chemical signals and mechanical signals. Due to a highly viscous environment, cells need to permanently produce forces in order to move. Cells achieve active movement by very different mechanisms. Many less complex prokaryotic organisms (and sperm cells) use flagella or cilia to propel themselves. Eukaryotic cell migration typically is far more complex and can consist of combinations of different migration mechanisms. It generally involves drastic changes in cell shape which are driven by the cytoskeleton, for instance a series of contractions and expansions due to cytoplasmic displacement. Two very distinct migration scenarios are crawling motion (most commonly studied) and blebbing motility.
The migration of cultured cells attached to a surface is commonly studied using microscopy. As cell movement is very slow (only a few µm/minute), time-lapse microscopy videos are recorded of the migrating cells to speed up the movement . Such videos reveal that the leading cell front is very active with a characteristic behavior of successive contractions and expansions. It is generally accepted that the leading front is the main motor that pulls the cell forward .

Cell migration directed by spatial cues, or taxis, is a primary mechanism for orchestrating concerted and collective cell movements during development, wound repair, and immune responses.  Mesenchymal cells possess a distinctive organization of the actin cytoskeleton and associated adhesion complexes as its primary mechanical system, generating the asymmetric forces required for locomotion without strong polarization. The emerging hypothesis is that the molecular underpinnings of mesenchymal taxis involve distinct signaling pathways and diverse requirements for regulation. 16

Cell migration is a fundamental process that occurs during embryo development. Classic studies usingin vitro culture systems have been instrumental in dissecting the principles of cell motility and highlighting how cells make use of topographical features of the substrate, cell-cell contacts, and chemical and physical environmental signals to direct their locomotion. 17 Motility bias relies on the induction of front-to-back cell polarity, which involves actin polymerisation at the cell front and the stabilisation of protrusion formation towards the signal. These events are frequently mediated by signal transduction events downstream of receptor activation that modulate the activity of small GTPases and actin dynamics. The transmission of membrane tension across the migrating cell also plays an instructive role in directing polarised motility. All the aforementioned processes show tight genetic regulation during development with respect to both the timing of cellular events and the spatial configurations of environmental signals. Such genetic control pre-configures the substrate landscape and determines the possible response mechanisms that cells can activate to direct their migration. However, migrating cells can also self-organise the chemical and physical substrate to which they will respond (e.g. by self-generating a chemoattractant gradient). In addition, cells can generate patterns of migration through interactions with other migrating cells (e.g. by means of contact inhibition of locomotion). The latter migratory events are not pre-configured and thus represent emerging properties of the system. 

4. Regulation and expression of differentiated cell functions
Developing animals face two main challenges. First, they must produce different types of proteins and cells and, second, they must get those proteins  and cells to the right place at the right time.  Davidson has shown that embryos accomplish this task by relying on networks of regulatory DNA-binding proteins (called transcription factors) and their physical targets.  18

The coordination of above mentioned points results partially from a complex network of communication between cells in which signals produced affect target cells where they are transduced into intracellular biochemical reactions that dictate the physiological function of the target cell 10 

The basis for the coordination of the physiological functions within a multicellular organism is intercellular signaling (or intercellular communication), which allows a single cell to influence the behavior of other cells in a specific manner. As compared to single-cell organisms, where all cells behave similarly within a broad frame, multicellular organisms contain specialized cells forming distinct tissues and organs with specific functions. Therefore, the higher organisms have to coordinate a large number of physiological activities such as:  

Intermediary metabolism  
Response to external signals  
Cell growth  
Cell division activity  
Differentiation and development
Coordination of expression programs  
Cell motility  
Cell morphology

Properties of signalling pathways 
Cell–cell interactions through signal-transduction pathways are crucial in the coordination of embryonic development. Typically, signalling pathways are activated by the binding of a ligand to a transmembrane receptor, which in turn leads to the modification of cytoplasmic transducers. Subsequently, these transducers activate transcription factors that ultimately alter gene expression. One of the most surprising findings about signalling processes is that only a few pathways are involved in and are responsible for most of animal development

Signals generated during intercellular communication must be received and processed in the target cells to trigger the many intracellular biochemical reactions that underlie the various physiological functions of an organism. Typically, a large number of steps is involved in the processing of the signal within the cell, which is broadly described as intracellular signaling. Signal transduction within the target cell must be coordinated, fine-tuned and channeled within a network of intracellular signaling paths that finally trigger distinct biochemical reactions and thus determine the specific functions of a cell. Importantly, both intercellular and intracellular signaling are subjected to regulatory mechanism that allow the coordination of cellular functions in a developmental and tissue-specific manner.

Despite the bewildering number of cell types and patterns found in the animal kingdom, only a few signalling pathways are required to generate them.  One clear conclusion to be drawn from all these studies is that there is a rather limited number of signalling pathways to generate the remarkable variety and complexity of form and function that we see today, both across phyla and within the individuals of a given species. 26 Understanding how these pathways have emerged and function can thus illuminate the origin of morphological diversity, as well as the molecular and cellular basis of development and disease. Amongst the central canon of developmental signalling pathways are the 

Hedgehog (Hh) 
Wingless related (Wnt) 
Transforming growth factor-β (TGF-β)
Receptor tyrosine kinase (RTK) 
Notch
Janus kinase (JAK)/signal transducer  
Activators of transcription (STAT) protein kinases
Nuclear hormone pathways
Bone morphogenetic proteins (BMP)
Epidermal growth factor receptors (EGFR)
Fibroblast growth factors (FGF)

Presence and absence of key signalling pathway components in Placozoans, Ctenophores, Sponges (Amphimedon and/or Oscarella) and non-metazoans (Monosiga and/or Dictyostelium).
White: absent, 
black: present, 
grey: not analysed, 
y: yes, 
n: no, 
y* indicates presence weakly supported by phylogenetic or domain composition analysis

                                                                               Trichoplax   Mnemiopsis  Amphimedon Monosiga 
                                                                                                                   (Choanoflagellate)








Schematic representations of the major metazoan developmental signalling pathways



Hedgehog
The  conserved Hedgehog (Hh) pathway is essential for normal embryonic development and plays critical roles in adult tissue maintenance, renewal and regeneration.The Hedgehog (Hh) family of proteins control cell growth, survival, and fate, and pattern almost every aspect of the vertebrate body plan. 29 The Hh gradient is shaped by several proteins that are specifically required for Hh processing, secretion, and transport through tissues. The primary cilium is crucial for mammalian Hedgehog signaling 30
Germline mutations that subtly affect Hh pathway activity are associated with developmental disorders, whereas somatic mutations activating the pathway have been linked to multiple forms of human cancer. The misregulation or mutation of essential core components of the Hh pathway often result in congenital birth defects, such as polydactyly and holoprosencephaly. In adults, the inappropriate activation of Hh signaling leads to cancer, the most common type being basal cell carcinoma.  



20

Wnt signaling pathway
The Wnt signaling pathway is an ancient and evolutionarily conserved pathway that regulates crucial aspects of cell fate determination, cell migration, cell polarity, neural patterning and organogenesis during embryonic development. 5

21

Transforming growth factor-β (TGF-β)
Transforming growth factor-β (TGF-β) superfamily signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems. 6

22

Receptor tyrosine kinase
Tyrosine phosphorylation is an essential element of signal transduction in multicellular animals. 7

23

Notch
Notch signaling is an evolutionarily conserved pathway in multicellular organisms that regulates cell-fate determination during development and maintains adult tissue homeostasis. 8

24

JAK/STAT 
Cell-cell signaling represents an essential hallmark of multicellular organisms, which necessarily require a means of communicating between different cell populations, particularly immune cells. Cytokine receptor signaling through the Janus kinase/Signal Transducer and Activator of Transcription/Suppressor of Cytokine Signaling (CytoR/JAK/STAT/SOCS) pathway embodies one important paradigm by which this is achieved.

25

Nuclear hormone pathways
The nuclear receptor superfamily are ligand-activated transcription factors that play diverse roles in cell di erentiation/development, proliferation, and metabolism and are associated with numerous pathologies such as cancer, cardiovascular disease, infl ammation, and reproductive abnormalities. 

Bone morphogenetic proteins (BMP)
Bone Morphogenetic Proteins (BMPs) are a group of signaling molecules that belongs to the Transforming Growth Factor-β (TGF-β) superfamily of proteins. Initially discovered for their ability to induce bone formation, BMPs are now known to play crucial roles in all organ systems. BMPs are important in embryogenesis and development, and also in maintenance of adult tissue homeostasis. 27 



Since all seven signal transduction pathways are essential for multicellular development  : is it feasable to suppose that they were all co-opted or borrowed from uncellular organisms ? If so, they still need the information to direct new body plan development. Where did this information come from ? 



References
1) http://www.mun.ca/biology/desmid/brian/SignallingEvolution.pdf
2) Gilbert, S. F. & Bolker, J. A. in Homologies of Process and Modular Elements of Embryonic Construction (ed. Wagner, G. P.) 435–454 (Academic, San Diego, California, 2001).
3) Gerhart, J. 1998 Warkany lecture: signaling pathways in development. Teratology 60, 226–239 (1999).
4) http://www.cellsignal.com/contents/science-pathway-research-stem-cell-markers/hedgehog-signaling-pathway/pathways-hedgehog
5) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2634250/
6) http://www.cellsignal.com/contents/science-pathway-research-stem-cell-markers/tgf-smad-signaling-pathway/pathways-tgfb
7) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358447/
8  http://www.cellsignal.com/contents/science-pathway-research-stem-cell-markers/notch-signaling-pathway/pathways-notch
9) http://www.ncbi.nlm.nih.gov/pubmed/26897340
10) http://www.wiley-vch.de/books/sample/3527333665_c01.pdf
11) http://www.cellsignal.com/common/content/content.jsp?id=pathways-nuclear
12) http://www.sciencedirect.com/science/article/pii/S0092867413010842
13) http://phys.org/news/2012-10-factors-cell.html
14) http://www.the-scientist.com/?articles.view/articleNo/38404/title/Taking-Shape/
15) Source: Boundless. “Cell Migration in Multicellular Organisms.” Boundless Biology. Boundless, 26 May. 2016.  https://www.boundless.com/biology/textbooks/boundless-biology-textbook/gene-expression-16/regulating-gene-expression-in-cell-development-117/cell-migration-in-multicellular-organisms-467-13125/
16) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177959/
17) http://dev.biologists.org/content/141/10/1999
18) http://reasonandscience.heavenforum.org/t2194-control-of-gene-expression-and-gene-regulatory-networks-point-to-intelligent-design
19) http://reasonandscience.heavenforum.org/t2316-where-do-complex-organisms-come-from#4782
20) http://www.genome.jp/kegg-bin/show_pathway?org_name=ko&mapno=04340&mapscale=&show_description=hide
21) http://www.genome.jp/kegg-bin/show_pathway?hsa04310
22) http://www.genome.jp/kegg-bin/show_pathway?org_name=ko&mapno=04350&mapscale=&show_description=hide
23) http://www.genome.jp/kegg-bin/show_pathway?org_name=ko&mapno=04012&mapscale=&show_description=hide
24) http://www.genome.jp/kegg-bin/show_pathway?org_name=ko&mapno=04330&mapscale=&show_description=hide
25) http://www.genome.jp/kegg-bin/show_pathway?org_name=ko&mapno=04630&mapscale=&show_description=hide
26) [url=http://zider.free.fr/papers/Paper (13).pdf]http://zider.free.fr/papers/Paper%20(13).pdf[/url]
27) http://www.sciencedirect.com/science/article/pii/S2352304214000105
28) http://www.genome.jp/kegg-bin/show_pathway?org_name=ko&mapno=04350&mapscale=&show_description=hide
29) http://genesdev.cshlp.org/content/22/18/2454.full
30) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2882129/
31) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150914/
32) Handbook of Cell signaling, page 85

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The  essential signaling pathways for animal development

http://reasonandscience.heavenforum.org/t2351-the-essential-signaling-pathways-for-animal-development

Cell signaling is arguably the most important characteristic of multicellular organisms.  Without cell signaling, the different cells in the body of a plant or animal could not communicate with each other, and they could not coordinate their actions. Such coordination is essential: first, to build a complex body composed of thousands or millions of cells and second, for the correct performance of such a body in everyday life, whether acquiring nutrients, excreting toxins, or dealing with hostile or friendly interactions from other organisms. This coordination is corroborated by the many problems and diseases (such as developmental abnormalities and cancers) that arise from malfunction of the cellular machinery that deals with cell signaling and communication. Thus, the study of such cell signaling machinery is receiving a great deal of attention by biological and medical research. At the most basic level, any cell signaling process must involve a signal, synthesized or otherwise, generated by the sending cell and some kind of system to receive that signal and respond to it in the receiving cell.

Less attention than this issue deserves,  has been given in the evolution/ID debate to elucidate  how cell signal transduction pathways function, what mechanisms, kind of molecules and proteins  are involved,, in what organisms they first emerged, and how these extremely complex and multifaceted  pathways could have possibly emerged, and what causes explain best their origins.  

If macroevolution involves changing morphological features, then the altering of signal transduction pathways becomes critical for any discussion of large scale evolution.

Signalling pathways are  complex networks of interactions. Surprisingly, only a few classes of signalling pathways are sufficient to pattern a wide variety of cells, tissues and morphologies. The specificity of these pathways is based on the history of the cell (referred to as the ‘cell’s competence’), the intensity of the signal and the cross-regulatory interactions with other signalling cascades.

Despite the bewildering number of cell types and patterns found in the animal kingdom, only a few signalling pathways are required to generate them.  One clear conclusion to be drawn from all these studies is that there is a rather limited number of signalling pathways to generate the remarkable variety and complexity of form and function that we see today, both across phyla and within the individuals of a given species. Understanding how these pathways have emerged and function can thus illuminate the origin of morphological diversity, as well as the molecular and cellular basis of development and disease. Amongst the central canon of developmental signalling pathways are the :

Hedgehog (Hh)
Wingless related (Wnt)
Transforming growth factor-β (TGF-β)
Receptor tyrosine kinase (RTK)
Notch
Janus kinase (JAK)/signal transducer  
Activators of transcription (STAT) protein kinases
Nuclear hormone pathways
Bone morphogenetic proteins (BMP)
Epidermal growth factor receptors (EGFR)
Fibroblast growth factors (FGF)

Hedgehog
The  conserved Hedgehog (Hh) pathway is essential for normal embryonic development and plays critical roles in adult tissue maintenance, renewal and regeneration.  The Hedgehog (Hh) family of proteins control cell growth, survival, and fate, and pattern almost every aspect of the vertebrate body plan. The Hh gradient is shaped by several proteins that are specifically required for Hh processing, secretion, and transport through tissues. The primary cilium is crucial for mammalian Hedgehog signaling

Wnt signaling pathway
The Wnt signaling pathway is an ancient and evolutionarily conserved pathway that regulates crucial aspects of cell fate determination, cell migration, cell polarity, neural patterning and organogenesis during embryonic development.

Transforming growth factor-β (TGF-β)
Transforming growth factor-β (TGF-β) superfamily signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems.

Receptor tyrosine kinase
Tyrosine phosphorylation is an essential element of signal transduction in multicellular animals.

Notch
Notch signaling is an evolutionarily conserved pathway in multicellular organisms that regulates cell-fate determination during development and maintains adult tissue homeostasis.

JAK/STAT
Cell-cell signaling represents an essential hallmark of multicellular organisms, which necessarily require a means of communicating between different cell populations, particularly immune cells. Cytokine receptor signaling through the Janus kinase/Signal Transducer and Activator of Transcription/Suppressor of Cytokine Signaling (CytoR/JAK/STAT/SOCS) pathway embodies one important paradigm by which this is achieved.

Bone morphogenetic proteins (BMP)
Bone Morphogenetic Proteins (BMPs) are a group of signaling molecules that belongs to the Transforming Growth Factor-β (TGF-β) superfamily of proteins. Initially discovered for their ability to induce bone formation, BMPs are now known to play crucial roles in all organ systems. BMPs are important in embryogenesis and development, and also in maintenance of adult tissue homeostasis.

Since all seven signal transduction pathways are essential for multicellular development  : is it feasable to suppose that they were all co-opted or borrowed from uncellular organisms ? If so, they still need the information to direct new body plan development. Where did this information come from ?

Most signal-relay stations we know about were intelligently designed. Signal without recognition is meaningless. Communication implies a signalling convention (a “coming together” or agreement in advance) that a given signal means or represents something: e.g., that S-O-S means “Send Help!” The transmitter and receiver can be made of non-sentient materials, but the functional purpose of the system always comes from a mind. The mind uses the material substances to perform an algorithm that is not itself a product of the materials or the blind forces acting on them. Signal sequences may be composed of mindless matter, but they are marks of a mind behind the intelligent design.

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