2016 Group Project 6
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|Signalling: 1 Wnt | 2 Notch | 3 FGF Receptor | 4 Hedgehog | 5 T-box | 6 TGF-Beta|
|2016 Group Project Topic - Signaling in Development
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|This page is an undergraduate science embryology student project and may contain inaccuracies in either descriptions or acknowledgements.|
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Transforming Growth Factor-Beta (TGF-β) Signalling Pathway
The transforming growth factor beta (TGF-β) is a multifunctional and pleiotropic cytokine. The TGF-β signalling pathway is crucial to the control of different biological and pathological processes, such as cellular proliferation and differentiation, angiogenesis, immune regulation/inflammation, apoptosis and cell survival.
TGF-β belongs to the Transforming Growth Factor superfamily - a large group of structually connected cell regulatory proteins. It consists of TGF-β 1, 2 AND 3, Growth Differentiation Factors (GDFs), Activins, Inhibins, Bone Morphogenetic Proteins (BMPs), Glial-derived Neurotrophic Factors (GDNFs) and Mullierian Inhibiting Substance (MIS). Most importantly, TGF-β plays a dominant part in the development of the embryo and adult organism.
This wiki aims to present a helpful overview of the TGF-β signalling pathway, but is in no means a complete resource on all information regarding the topic. This site focuses on particular aspects of the pathway, such as its history, process, regulation, significance in embryonic development, animal studies and abnormalities.
Since the early stages of the TGF beta-signaling pathway, plenty of in-depth research and studies have been conducted that have no doubt contributed to our knowledge of the pathway today.
SMAD signaling and the three receptors for TGF-beta are two of the many fields of interest regarding the topic. In medicine and specific areas such as cancer, cardiovascular disease and inflammatory bowel disease, there are numerous alternatives for drugs that can either heighten or suppress the activity of TGF-beta.
|1988||The process of maturation of follicle-enclosed oocytes and cumulus-oocyte complexes was sped up by TGF beta. It was discovered that TGF beta and other growth factors are effective in vitro stimulators of oocyte maturation in the rat|
|1989||It was already known that TGF-beta 1 is a strong autocrine growth inhibitor of lymphocytes. Ellingsworth and colleagues found that TGF-beta 1 binds to all three cell surface-binding proteins (280-200 kD, 95-85 kD, 65 kD).
It was also found that these binding proteins are required for signal transduction. Overall, they discovered that the regulation of the expression of the TGF-beta 1 receptor is controlled by T cell mitogenic signals. 
|1989||It was made known that the properties of R mutants classify TGF-beta type I binding protein as the receptor involved in mediating TGF-beta actions on cell adhesion and proliferation|
|1989||Drosophil was the only member of the TGF-beta family to be identified in invertebrates|
|1990||It was already known that the rapid increase in number response of mink lung epithelial cells to serum and to epidermal growth factor was inhibited by TGF beta 1. A necessary component of TGF-beta 1 mediated growth inhibition in CCL64 epithelial cells is the coupling of TGF beta 1 receptor binding to G-protein activation|
|2000||VegT function was found to be involved in sequence with the TGF beta pathway. Therefore, TGF beta signaling may be activated by the maternally expressed VegT to participate in endoderm determination|
|2005||Within the TGF beta superfamily, it was found that a limited number of type I and type II receptors worked together to produce specificity of action|
|2010||Deregulation of TGF beta signaling was reported in human psoriasis|
|2015||It was known that TGF is required in the tumorigenicity and metastasis of bone tumour. A significant event in the activation of the TGF beta signaling pathway is the binding of transcription coactivator Yes-associated protein (YAP) to Smad transcription factors|
In the canonical pathway, the dormant TGF-β complex is formed when the three TGF-β ligand isoforms - TGF-B1, TGF-B2 and TGF-B3 - bind once it is synthesized as precursors. After secretion and extracellular activation, TGF-β ligands can bind to two types of receptors: the membranous TGF-β type III receptor or the TGF-β type II receptor (TGF-βRII) homodimers with high affinity. TGF-βRII binding enables dimerization with TGF-β type I receptor (TGF-βRI) homodimers, as well as activation of the TGF-βRI kinase domain and signal transduction across phosphorylation of the C-terminus of receptor-regulated SMADs, SMAD2 and SMAD3. A heterotrimeric complex is formed by the TGF-βR dimer and SMAD4, which moves and assemblies in the nucleus. TGF-β dependent signalling can operate or subdue numerous target genes through the communication of SMADs with multiple transcription factors. There are many structures in which SMAD activities are regulated, such as SMAD2/3 nucleocytoplasmic shuttling, binding to anchor proteins, phosphorylation and Smurf (SMAD-ubiquitination-regulatory factor). 
In the non-canonical pathway, SMAD-independent pathways such as PI3K/AKT and MAPK pathways like ERK, JNK, and p38 MAPK are activated by TGF-β signalling. In addition, transversal signalling, especially at the SMAD level, allows TGF-β pathway activation to incorporate signals from integrins, Notch and Wnt dependent pathways as well as signals from cellular processes like the cell cycle or apoptosis machineries. Thus, the TGF-β signalling pathway has pleiotropic functions regulating cell growth, differentiation, apoptosis, cell motility, extracellular matrix production, angiogenesis and cellular immune response.
Process of TGF-β signalling pathway
TGF-β signalling pathway is required for regulation of a large number of cellular processes such as cell proliferation, invasion and inflammation. It is also activated mitogen activated protein kinase signalling. There are two main routes in TGF-β signalling; the SMAD Dependent pathway and SMAD Independent pathway.
SMAD Dependent TGF-β signalling pathway
The ligands of the TGF-β superfamily form dimers that bind to heterodimeric receptor complexes composed of two type I and two type II transmembrane receptor subunits with serine/threonine kinase domains. Following ligand binding on TGF-β1, the dimerized TGF-β type II receptors phosphorylates and activates the TGF-β type I receptors. In most cell types, this leads to recruitment and phosphorylation of the receptor-regulated SMAD2 and SMAD3, presented by the SMAD anchor for receptor activation. SMAD1 and SMAD5 can be activated by the TGF-β signaling depending on the Type I receptor that is expressed. Heterologous complexes are formed by the phosphorylated receptor-regulated SMAD with the common-mediator SMAD, SMAD4, and successively move into the nucleus, where they accumulate and act as transcription factors participating in the regulation of target gene expression. In addition, they recruit extra transcriptional regulators, such as DNA-binding transcription factors, co-activators and co-repressors. These control the expression of several target genes and ultimately initiates a SMAD-dependent signaling cascade that induces or represses transcriptional activity. SMADs are widely expressed in most adult tissue and cell types, indicating that the TGF-β signaling pathway is ubiquitous.
SMAD independent TGF-β signalling pathway
Rather than SMAD-mediated transciption TGF-β also has the potential to activate other signalling cascades for example the Erk, JNK and p38 MAPK kinase pathways. In some cases these pathways exhibit activation with slow kinetics which indicates SMAD-dependant mechanics, however there has also been rapid activation cases (5-15mins) suggesting independence from transcription mechanisms. Studies carried out with SMAD4 deficient cells and dominant-negative SMADS provide evidence that the MAPK pathway activation is independent from SMADS, as well as this it has be found that p38 MAPK signalling was activated in response to mutated TGF- β type 1 receptors, which were defective in SMAD activation.
The precise mechanisms and biological consequences of these SMAD-Independent pathways (Erk, JNK, p38 MAPK) are currently poorly characterized. Ras is implicated in TGF- β induced Erk signalling as there is rapid activation of Ras by TGF- β in epithelial cells. The JNK and p38 MAPK signalling are activated by various MAPK kinase kinases (MAPKKK) TGF- β kinase 1 (TAK 1) receptor is a MAPKKK family member. Further research and identification of various interactions between the small signalling molecules and receptor proteins will provide additional insight into the precise mechanism behind the activation of MAPK pathways by TGF- β ligands .
Regulation of the pathway and factors affecting it
Signalling mechanisms by TGF-β like factors are regulated in both negative and positive fashions, these are all tightly controlled through a multitude of mechanisms at extracellular, membrane, cytoplasmic and all the way to nuclear levels. Positive regulation is required to amplify signalling from TGF-β like factors, while negative regulation is important for the termination and restriction of signalling usually occurring through the mechanism of a feedback loop. There is also additional regulation of TGF-β like factors via cross-talk with other signal transduction pathways such as MAPK and JAK/STAT pathways.
The positive regulation of TGF-β specifically the induction of ligands and their signalling components often is triggered by the action TGF-β-like factors themselves. For example NODAL, a secretory protein of the TGF-β superfamily which plays a role in early embryogenesis and acts through activin receptors and SMAD2 is induced by nodal signalling itself. In other types of cells TGF-β receptors as well as transcription factors which serve as targets for TGF-β like factors can be induced by ligand stimulation, as identified in case of transcription factor Runx3 which is induced by TGF-β and forms a complex with SMAD3 to be further activated by TGF-β. The mechanism of SMAD signalling is also positively modulated via the "cross-talk" (and hence the process of SMAD dependant TGF-β signalling) with other signalling pathways, SMADS may be activated by the tyrosine kinase receptor under specific circumstances and further positively regulate TGF-β like factors .
Signalling is regulated at the cell membrane level as well as within the cytoplasm of the cell, specifically by BAMBI, a pseudo-receptor for serine/threonine kinase receptors (in Xenopus embryos however displays a high degree of sequence similarity to human BAMBI gene). This BAMBI receptor is structurally alike to the type 1 serine/threonine kinase receptor, the only difference being that it lacks an intracellular domain. BAMBI has shown a similar expression profile to that of BMP-4 a growth factor from the TGF-β super family, and has been found to require BMP signalling for expression. BAMBI when goes on to interact with both type 1 and type 2 serine/threonine receptors and works to abolish their abilities to signal via BMPs, activins and TGF-βs, therefore it is postulated that BAMBI can be inductively expressed by BMPS to self regulate BMP signalling as well as cross-regulate signalling from other members of the TGF-β super family. 
Significance in Embryonic Development
TGF betas are involved in embryogenesis. During development of the embryo, members of the TGF-beta family are essential for bone and cartilage formation, mesoderm induction and patterning and dorso-ventral patterning.
Genetic engineering and tissue explanation studies have revealed many roles for TGF-β ligands and their signaling molecules in development. In the embryo, TGF-β appear to be involved in epithelial-mesenchymal transformations (EMT) during the formation of endocardial cushions, and in epicardial epithelial-mesenchymal transformations essential for coronary vasculature, ventricular myocardial development and compaction. It must be noted that in the normal function of the cardiovascular system in the adult, TGF-β play significant roles in cardiac hypertrophy, vascular remodeling and regulation of the renal renin-angiotensin system.
TGF-β1 is expressed in the endocardium of the developing mouse. TGF-β(-/-) mice have been found with obvious congenital cardiovascular defects, so it’s important to review its expression in the developing heart. In the blood vessels, TGF-β1 is in the intima whereas TGF-β2 and TGF-β3 are in the media and adventitia. TGF-β2 signals are found as early as embryonic day 7.25 (E7.25) in the cardiogenic plate of the precardiac mesoderm and is later prominent in the myocardium of the aortic sac and outflow track regions. TGF-β2 protein is also found in the entire myocardium of the heart at the time when looping occurs. From E8.5-9.5 when the cushion formation process occurs, there is a particularly strong TGF-β2 expression localised to the myocardium as displayed in A, B, D and E in the figure. After cushion formation and EMT, and before myocardialization of the endocardial cushion begins, there is also strong TGF-β2 expression in the OT myocardium and in the adjacent developing cushion mesenchym. However, as myocardialization occurs, TGF-β2 expression is reduced in the myocardium so that from E12.5 onwards, it is only expressed mainly in the mesenchyme of the cushion and OT septum. As can be seen in 2GH, TGF-β2 expression remains high in the cushion mesenchyme of the OT septum. By E15.5, TGF-β1 s now the most highly expressed isoform in the endocardial cells of the myocardium. It is seen in M, N, O of the figure that the epidcardium TGF-β1 and TGF-β3 expression is higher than that of TGF-β2. Thus, it can be seen that all three TGF-β are expressed in the epicardium, and they are not expressed in an overlapping fashion.
Cross talk between mesoderm and underlying endoderm is needed to form the early tubular heart. This cellular and molecular induction in the primary heart forming regions is important for the specification and differentiation of myocardial and endocardial precursor cells. Other endoderm-derived growth factors such as BMP2, FGF2 as well as TGFBS have been implicated in this process in the avian system. TGFB2 and TGFB receptors are expressed in the precardiac mesoderm along with BMP2. Members of the TGG family can serve as inductive signals at the heart forming fields for the formation of myocardial and endocardial precursor cells. Members such as Activin, BMP, Nodal, Left and others have been found to be crucial for the establishment of embryonic asymmetry , and this asymmetry is in turn critical for heart development .
Mammary Gland Development
Similarly, all three TGF-β isoforms are expressed during all stages in the development of the mammary gland except lactation. Specifically, mouse studies have indicated key roles for TGF-β in organizing the architecture of the mammary gland, regulating stem cell kinetics, inducing apoptosis in the involuting gland and maintaining the epithelium in a functionally undifferentiated state. The TGF-β isoforms are expressed in the ductal epithelium at all stages of development and some reviews have found that there may be some isoform specificity for temporal and spatial expression patterns . For example, TGF-β3 is the only isoform present in the endbup cap cells and myoepithelial cells. Additionally, TGF-β1 is present at high levels in the extracellular matrix that surrounds growth-quiescent ducts. As for its effect, TGF-β have been to have induce multiple responses such as inhibiting the proliferation of mammillary epithelial cells. The nature of the target cell of plays a role as TGF-β also induced apoptosis without the inhibiting the proliferation. This highlights the highly variable actions of TGF-β that are affected by cell type, environmental and cell history to name a few. Interestingly, TGF-β have been implicated as both tumour suppressors and oncogenes in mammary tumorigenesis. For example, the overexpression of TGF-β1 inhibits tumorigenesis whilst interfering with its receptor function enhances tumorigenesis, thus hinting at its tumor suppressor role . On the contrary, TGF-β has exhibited the enhancement of tumorigenesis as the TGF-β ligand expression is increased in late human breast cancer. Thus, TGF-β further proves its pleiotropic behaviour as prevalent to the mammary gland as it potentially suppresses and/or promotes tumorigenesis.
Maintenance of pluripotency in hESC
Many of the members within the TGF-β superfamily are enriched within stem cells suggesting they play an important role in these cells, specifically relation to their pluripotency. The ability for a cell to self renew and differentiate is known as 'stemness', the stemness of human as well as mouse embryonic stem cells can be maintained by growing a combined culture with feed cells for example, bone morphogenic protein 4 (BMP4) induces a helix-loophelix-protein known as Id which is a potent inhibitor of differentiation, since this BMP (a member of the TGF-β superfamily) is a potent inhibitor of neural differentiation in vertebrate embryos it is thought to maintain the stemness of hESCs and thus maintain their pluripotency.
The nodal secretory protein from the TGF-β superfamily were found to also contribute to mESC pluripotency, this was evidenced by microarray of Nodal deficient mice which were found to have diminished levels of Oct3/4 (transcription factors)expression, which are markers of undifferentiated stem cells. More importantly a nuclear localization of SMAD2 was found in hESCs, this is generally induced by TGF-β, activin or nodal signalling. Further microarray analysis identified that activin supposedly maintains the pluripotency of hESCs through inducing the expression of Oct4 as well as Nanog both transcription factors which are heavily involved in the self renewal of undifferentiated embryonic stem cells. Consistent with this finding, the subsequent inhibition of SMAD2 phosphorylation resulted in the decrease of expression of the markers of undifferentiated ESCs (Oct3/4, Nanog), suggesting that these were a product of SMAD2 phosphorylation and because SMAD2 is a product of activin/nodal signalling further suggesting that activin or nodal proteins produced by ESCs function to promote the maintenance of pluripotency in hESCs..
Formation of the palate
The formation of the palate is a complex procedure which involves a multitude of events including palatal shelf growth, elevation as well as left and right side fusion, as a result of genetic defects this procedure can sometimes result in formation of a cleft palate, one of the most common genetic birth defects. There have been recent findings which indicate TGF-β signalling plays a prime role in regulating the development of the palate in regards to both the palatal mesenchyme and epithelium. In humans the palate develops from two primordiuims, the primary and secondary palate, these progress to develop into palatal shelves which are positioned vertically against each other along the sides of the tongue. Following jaw growth and descent of the tongue these primordial palates orientate themselves horizontally and begin to fuse, in the case of the hard palate the mesenchyme cells are replaced by intramembranous bone as opposed to the soft palate which remains muscular and does not undergo ossification. Alike to humans mice have a similar embryological process of palate formation with the stage of palatal fusion resulting in the formation of a medial edge epithelium (MEE) seam which eventually degrades via apoptosis, thus the mouse serves as a strong candidate to fulfil the role of a reliable animal model. 
With this model being established, it has been identified that TGF-β1 is strongly expressed in MEE cells just prior to adherence of the opposing palatal shelves, following this adherence the level of TGF-β1 gradually decreased until it ceased to be expressed in the mesenchymal cells, TGF-β. TGF-β2 and TGF-β3 were also expressed in the palatal mesenchymal cells during adherence and TGF-β3 was found to be continually expressed during the fusion process, it is further found that TGF-β3 played a crucial role in the cell degradation of MEE cells in addition to palatal fusion. It was found that when TGF-β3 deficient mice developed they expressed defects in MEE seam degradation and fusion..
The use of these animal models to explore the role of TGF-β in cleft palate formation is fruitful in terms of identifying contributing factors and subtypes of TGF-β family members however there still remains much to discover of the molecular and cellular mechanisms associated with palate formation.
Animal studies have served as a useful way in providing pivotal information regarding the mechanisms of TGF-β action in wound healing. In fact, much of the current information on the action of TGF-β in wound healing has been acquired from animal studies using incisional and/or excisional wounding models and manipulation of TGF-β signalling by adding the exogenous TGF-β protein or anti-TGF-β neutralizing antibodies, or by genetic alteration in components of the TGF-β signalling pathway.
This is due to the fact that animal models provide outstanding experimental methods for explaining molecular mechanisms by which TGF-β regulates wound-healing responses. Ultimately, it has led the development of therapeutic strategies focusing on how the TGF-β pathway can improve wound healing and scarring outcome.
Wound healing is an intricate physiological process distinguished by the successive overlapping stages of inflammation, proliferation and maturation. It that requires numerous growth factors, one of which includes TGF-β, which has the widest range of effects. TGF-β is a multifunctional growth factor that employs pleiotropic effects on wound healing by regulating cell differentiation, extracellular matrix production and immune modulation. The role of TGF-β signalling in wound healing was explored through examination of the development of tissue-specific expression systems for overexpression or knockout of TGF-b signalling pathway components. This study also classified that molecules might serve as molecular targets for the treatment of pathological skin conditions such as chronic wounds and excessive scarring (fibrosis). Exogenously added TGF-β has the potential to promote wound healing by stimulating angiogenesis, immune cell infiltration, and ECM production, and that diminishing endogenous TGF-β action reduces scarring without adversely affecting wound-healing quality.
Interpreting wound-healing results obtained from the animals brought about its limitations. For instance, an underlying skin abnormality was found on many of the mouse models with genetic alterations in the TGF-β signalling pathway. Also, the pleiotropic effects of TGF-β on many different cell types throughout stages of wound healing highlighted a challenge in designing particular methods in which the TGF-β signalling pathway can assist wound healing or reduce scarring. 
Direct modulation of TGF-β levels
Injecting TGF-β into normal skin of newborn mice led to resilient initiation of angiogenesis and fibrosis. This consisted of important new collagen synthesis combined into the matrix. As a result of these observations, people were encouraged to further study the administration of TGF-β to incisional wounds in rats. It proved that TGF-β treatment resulted in better dermal healing, as showed by prominent collagen deposition and significantly increased wound strength.
TGF-β1 Null mice: An animal model for Inflammatory Disorders
Out of the number of TGF-β1 null (knockout) mice that are generated in the laboratory, it is estimated that around 60% die in utero and the 40% that survive develops normally to term. During the first 2 weeks of postnatal life, the mice appear normal and look healthy. However, after 3 to 4 weeks, they start to develop a rapid wasting syndrome, which is largely characterised by a great decrease in body weight gain in contrast with controls. At this point, the mice become inactive and appear sick with unhealthy looking fur. Some can survive up to 4 or 5 weeks. The healthy animals are separated from their mother as the mother has the responsibility to care for the sick animals. Surprisingly, it is the affected animals that have a longer life span.
All of the knockout mice have a multifocal inflammatory disease in many tissues. The heart and lungs were the organs that were affected to the greatest degree, following the stomach, colon and pancreas. No lesions in the TGF-B1 knockout mice were found in the animals that died during the first week of life. The earliest lesion was seen at 8 days of age in the lung and heart. It began in the heart with endocardial endothelial hypertrophy and mild infiltration of mononuclear inflammatory cells. During the next 14 days, the endocarditis became more severe and reached the myocardium and pericardium. The most dominant inflammatory cells were macrophages. Within the lung, chronic inflammatory infiltrates consist of T and B lymphocytes, including plasma cells, whereas macrophages are the primary inflammatory cell type in the heart. From day 8, it was possible to see increased expression of major histocompatibility complex class I and II proteins in pulmonary vascular endothelium, as well as an immunoblastic response in mediastinal and mandibular lymph nodes and spleen. In the absence of any pathogens, this massive inflammatory disease, together with overexpression of major histocompatibility complex class I and II proteins and overproduction of immunoglobulins by lymphocytes, offers circumstantial evidence for an autoimmune etiology.
Abnormalities of the TGF-Beta Pathway
Mutations or deletion of the TGF-beta 1 or TGF-beta RII gene have been associated with multiple syndromes. In mice, defects have been found in haematopoiesis, vasculogenesis and endothelial differentiation of extra embryonic tissues, while knockout mice for SMAD2 or SMAD4 genes are more likely to have spontaneous tumour development and excessive inflammatory responses. In humans, various diseases have been linked to the mutation of the TGF-beta RII gene and SMAD4 mutation is genetically responsible for familial juvenile polyposis, an autosomal dominant disease characterized by predisposition to gastrointestinal polyps and cancers.
Alterations of this signalling pathway are common in cancer. Accessory proteins such as soluble or membrane-bound regulators or co-receptors can also affect TGF-beta signalling. A normal acting cell has a functional TGF-β signalling pathway, in which TGF- β stops proliferation of cells at G1 stage to either encourage apoptosis or induce differentiation. If the TGF-β signaling pathway becomes mutated these cells can become cancerous as the TGF-β no longer controls the cell. Uncontrolled, these cancer cells proliferate and cause surrounding fibroblasts, immune cells, endothelial and smooth-muscle cells to proliferate as well. From this increased production of TGF-β it causes angiogenesis and immunosuppression, further propogating the cancer. The human body has an regulation against this, which is called effector T-cells which destroy cancer cells via an inflammatory reaction. However, TGF-β converts them into regulatory T-cells, which reduce the inflammatory reaction.
It is also suggested that TGF-β signaling has a large part to play in the pathogenesis of Marfan syndrome. This disease causes disproportionate height, abnormally long fingers and toes, displaced crystalline lens of the eye. Not only this but heart complications can also occur, like mitral valve prolapse or aortic enlargement. Marfan syndrome is generally known to be caused by defective creation of elastic fibres, more specifically of the glycoprotein fibrillin I. In a study done it was observed that by adding TGF-β antagonist in mice who were affected by Marfan syndrome phenotype, their symptoms were alleviated. From this, we can see that the mechanism involved in Marfan syndrome most likely has an underlying relation with lowered sequestration of TGF-β by fibrillin.
The TGF-B pathway has many effects on cardiomyocytes, mesenchymal and immune cells. Not only this, but it plays a vital role in the pathogenesis of cardiac remodeling and fibrosis. Abnormalities in this pathway can cause an overexpression of TGF-β which has been associated with fibrosis and hypertrophy in mice hearts. We see that endogenous TGF-β is capable of varying matrix metabolism in a pressure-overloaded heart. In a heart which has undergone great stress, such as myocardial infarction, TGF-β is seen to inactivate inflammatory macrophages. This allows for less of an immune response but further done by it encouraging myofibroblast transdifferentiation and matrix synthesis. Thus higher levels of TGF-β is causing more inflammatory damage and further propagating the heart disease. 
In Multiple Sclerosis (MS) a common observation is that patients will generally have lower levels of TGF-β, which is suspected to prevent remylentation of neurons. The reason why this is of significance is because MS results in demylentation of neurons causing severe neurological problems. TGF-β is normally responsible for regulating apoptosis of Th17 cells.Thus when TGF-β levels decrease due to abnormalities, they are not able to be regulating Th17 cells apoptosis. This then causes Th17 cells to secrete TNF-α, finally causing a demylenation of the oliodendroglial (neurons).By having a lower amount of TGF-β we get a higer level of Th17 cells and therefore more TNFα and neuronal damage. Thus we can observe that this pathway is vital in maintaining neuronal health.
Obesity, Diabetes and Hepatic Steatosis
Normally, TGF-β signaling pathway has a major role in maintaining a regulated level of glucose and energy under homeostatic conditions. Not only this, but TGF-B could also have a vital task in diabetic kidney disease.  Abnormalities in TGF-β signaling in obesity is one of the reasons why there is so much inflammatory damage in the human body by obesity.  This was shown again in a study done where mice affected were given a systemic blockade drug for the TGF-B pathway and it was observed that they were protected from obesity, diabetes and hepatic steatosis. 
Abnormalities of the TGF-β signaling can also cause Loeys–Dietz syndrome via mutations in the TGF-β receptor. Loeys-Deitz syndrome connective tissue disorder, mainly in children where there are aneurisms in the aorta. Not only this, but the aorta can undergo dissection in weakened layers of the aortic wall. Further, the disease is labelled into four different types, since it is an autosomal dominant genetic connective tissue disorder, the groups are categorized by their genetic cause. TGFB1 and TGFB2 cause type I and II. Normally these genes allow for the fruition of the body’s development and growth. However, when defective they create non-functioning proteins.
TGF-B Signalling Pathway Quiz - How well do you know it?!
|Apoptosis||Cell death which occurs as a normal and controlled part of an organism's growth or development|
|Avian system||Respiratory system that delivers oxygen and removes carbon dioxide|
|CCL-64||- mink lung epithelial cell|
|Cytokine||A broad and loose category of small proteins that are important in cell signalling|
|Cushion Formation||Cells in development that play a role in the formation of the heart septa|
|Dimer||An oligomer consisting of two structurally similar monomers joined by bonds that can be either strong or weak, covalent or intermolecular|
|Homodimers||A protein composed of two polypeptide chains that are identical in the order, number, and kind of their amino acid residues|
|Isoform||A protein that has the same function as another protein but which is encoded by a different gene and may have small differences in its sequence|
|Ligands||A molecule that binds to a larger molecule|
|Looping||A morphogenetic process when the heart shape is formed by looping the embryonic tube|
|Pleiotropic||To produce more than one type of effect|
|BMP||Bone Morphogenetic Protein, a protein part of the TGF-β superfamily.|
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