2016 Group Project 2

From Embryology
2016 Student Projects 
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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The Notch Signalling Pathway

Introduction

The Notch signalling pathway is the most prevalent form of intracellular communication in multicellular organism. The pathway is critical for cell differentiation, proliferation, and apoptosis. It is involved in embryonic organ development through the regulation of cell-cell signalling; specifically lateral inhibition, formation of boundaries, and cell lineage assignation.[1][2] This pathway is also actively involved in adjacent cell communication, developmental process such as adult homeostasis and stem cell maintenance. Since this pathway is an intricate and crucial aspect of an organisms development and cell signalling, a mutation in the functional components of this pathway can cause a myriad of diseases such as congenital disorders, cancers, strokes, Alagille syndrome and leukoencephalopathy.[3] The Notch signalling process primarily utilises a ligand- receptor interaction to release protein fragments at the cellular membrane that provide signals to the internal aspect of the cell and to the adjacent cells. In mammals, the Notch signalling pathway is comprised of four receptors (Notch 1-4) which interact with Delta or Jagged ligands to bring about the activation of this pathway.

<html5media width="560" height="315">https://www.youtube.com/embed/axkDX0XZyN0</html5media>


History

1914 First description of a "notch" defect (loss of tissue in the wing) in Drosophila by John S. Dexter, giving the gene its name
1917 First allele of Notch is identified by Thomas Hunt Morgan
1930s Donald F. Poulson conducts research into the involvement of Notch in development
1958 An investigation by W.J. Welshons confirmed that the locus of Notch is contained within the 3C7 band of the X chromosome.
1983 DNA sequences belonging to the Notch locus cloned and determined that RNA is required for the function of the wild type Notch. Further insight developed into the function of Notch and its role in differentiation and regeneration.
1986 The molecular analysis and sequence of the Notch locus was determined by Michael W Young and his team. A relationship was identified between the protein encoded by the major Notch transcript and mammalian clotting and growth factors
1989 Neurogenic loci "Delta" and "Mastermind" identified and research conducted to search for genes which may have an interaction with the Notch protein. It was confirmed that mutations in these loci will affect neurogenesis.

Overview of Molecular Mechanisms

Mammals possess a total of four Notch genes, with five genes for encoding the associated ligands, Delta-like and Jagged. The Notch genes each code for a single transmembrane receptor. Extracellularly, it contains epidermal growth factor (EGF)-like repeats for ligand interaction and Lin-12-Notch (LN) repeats for regulating the interactions between the extracellular and intracellular regions. Intracellularly, Notch has seven ankyrin (ANK) repeats and a transactivation domain (TAD), as well as a proline, glutamine, serine, threonine-rich (PEST) domain for degradation of Notch.

The structure of the Notch receptor.[3] Extracellularly there are epidermal growth factor (EGF)-like repeats and Lin-12-Notch repeats (LNRs). The Notch intracellular domain (NICD) is made up of a rRBP-Jkappa-associated module (RAM) domain, ankyrin (ANK) repeats, and a proline, glutamine, serine, threonine-rich (PEST) domain. There are three sites for cleavage by enzymes: S1, S2, and S3/S4.

Canonical pathway

Summary of canonical Notch signalling. The interaction between Delta-like or Serrate ligands (DSL) and the Notch receptor on an adjacent cell initiates proteolytic cleavage of Notch and the release of the Notch intracellular domain (NICD). The NICD is then transported to the nucleus where it can induce transcription of Notch target genes by binding to specific proteins (MAM, CSL).[4]

The canonical Notch pathway is unique in that it involves direct interaction between adjacent cells, as opposed to paracrine signalling, because both the Notch ligands and Notch receptors are transmembrane proteins found in the cell membrane. Furthermore, the lack of a secondary messenger or amplification process means that the Notch pathway has limited opportunities for regulation and must therefore be tightly controlled. Depending on its developmental and cellular context, activation or inhibition of the pathway can result in a variety of cellular responses, including cell death, proliferation, or differentiation.[5]

Four Notch proteins are involved in the canonical pathway. NOTCH1 to NOTCH4 are single transmembrane receptors and can interact with a variety of ligands, including NOTCH ligands (e.g. Delta ligands) and Serrate ligands. There are three Delta ligands (Dll1, Dll3, and Dll4) and two Serrate ligands (Jagged1 and Jagged2) present in mammals.[5] The binding between the Notch receptor and the ligand on the adjacent cell induces the release of the Notch intracellular domain (NICD) via a sequence of proteolytic reactions.[1] Cell-cell interaction is therefore critical in the process of triggering Notch signalling.

The interaction on the cell surface between Notch and its ligand on an adjacent cell causes the extracellular metalloprotease site (S2 site) to be exposed. The S2 site is then cleaved by transmembrane proteases belonging to the a disintegrin and metalloproteinase/tumour necrosis factor α converting enzyme (ADAM/TACE) family. The remaining Notch fragment subsequently undergoes two more intramembranous cleavages at the S3/S4 sites by the γ-secretase complex. Finally, the NICD is released and enters the nucleus to interact with CSL (CBF1, Suppressor of Hairless, Lag-1) and Mastermind-like proteins (MAMLs). CSL is a DNA-binding protein that acts as a transcription factor by forming repressor or activator complexes; in the absence of the NCID, CSL is bound to corepressor proteins (CoR) that prevent transcription of Notch target genes. MAMLs are transcriptional co-activators that are required for transcription of the target genes, hence they are involved in the regulation of the pathway.[2][5] To stop signalling, the NICD is phosphorylated by kinases and ubiquitinated by E3 ubiquitin ligases, which results in proteasome mediated degradation and subsequent termination of the signal.[5]

Non-canonical pathway


Transcriptional regulation of Notch signalling


Examples of Proteins Involved in Interaction with the Notch Intracellular Domain[6]

Protein Interaction with NICD
Adenamatous polyposis coli (Apc) Controls Notch trafficking
Cyclin-dependant kinase 8 (CDK8) Phosphorylates NICD to make it a substrate for ubiquitylation and degradation
CBF1, Su(H) and LAG-1/Recombination signal binding protein for immunoglobulin kappa J region (CSL/RBP-J) Main canonical transcriptional co-factor for NICD
Cyclin C (CycC) Targets NICD for phosphorylation to make it a substrate for ubiquitylation and degradation
Dishevelled (Dsh/Dvl) Controls ligand-independent Notch trafficking; inhibits canonical Notch signalling
Deltex-1-4 (Dtx1-4) Controls Notch ubiquitylation, processing, and internalisation
Itchy, E3 ubiquitin protein ligase (Itch) Promotes ubiquitylation of NICD
Mastermind-like 1/2 (Maml1/2) Co-activator for NICD/CSL
Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-ϰb) NICD blocks NF-ϰb transcription of NF-ϰb target genes through binding to p50/cRel
NICD enhances NF-ϰb transcription of target genes by retaining NF-ϰb in the nucleus
Numb homolog (Numb) Suppresses Notch signaling by recruiting E3 ubiquitin ligases to ubiquitylate Notch
Controls Notch trafficking during asymmetric cell division
Smad family members (SMAD) Smads enhance Notch signalling; Notch fine-tunes signalling through Smads


Roles in Embryonic Development

The phylogenetically conserved Notch signalling pathway plays a crucial role in the development of multiple organ systems, and is a major regulator of stem cell fate. It is responsible for the regulation of the transcription of a number of signalling molecules, such as MyoD, Mash1 and GATA2, which are genes controlling the fate of myogenic, neurogenic and haematopoietic stem cells, respectively. [7] The following subsections will further elucidate the vital roles of Notch signalling during normal embryonic development.

Cardiovascular

Cardiomyocyte Specification and Differentiation

Expression during the appropriate window of the timeline of embryogenesis of Notch receptors, ligands and downstream effector molecules elucidates a role for the Notch pathway in the earliest stages of cardiac development. It has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification as early as during gastrulation. [8] Interestingly, Notch has been found to play both suppressive and promoting roles in cardiogenesis.

For example, it has been shown that Notch suppresses cardiomyocyte cell fate specification during early cardiogenesis. This has been demonstrated through studies such as that carried out by Rones and colleagues (2000), which used activation and inhibition of Notch signaling in Xenopus. [9]

On the other hand, studies such as that by Boni and colleagues (2008) have found that Notch signalling may also promote myogenesis from cardiac progenitor cells. [7] Cardiogenesis has also been promoted by downregulating Notch-1 activity in stem cells of embryos (Nemir et al., 2006).[10]

Despite the understanding that Notch signalling is crucial to embryonic myogenesis, the exact molecular mechanism remains elusive. Research by Buas and colleagues (2010) has explored such mechanisms by studying the Notch target, Hey1, which is known to suppress myogenic differentiation. They concluded that this inhibitory function of Hey1 is primarily mediated through binding near to myogenin and Mef2C promoters, which leads to cessation of target gene expression. [11]

Simplified Scheme of the Roles of Notch in Cardiac Development
Simplified Scheme of the Roles of Notch in Cardiac Development. Notch has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification early in development. Further after cardiac differentiation, Notch influences development of the AVC (atrioventricular canal), cardiac valves, ventricular trabeculae and the cardiac outflow tract. (This student-drawn image is based upon Figure 2 in the 2014 review by Zhou and Liu: Role of Notch signaling in the mammalian heart.[12])

Development of the Atrioventricular Canal

A study by Rutenberg and colleagues (2006) and another by Kokubo and colleagues (2007) implicate a role for Notch signaling in the region between the atria and the ventricles of the heart (the atrioventricular canal, or AVC).[13] [14] They used chicken and mouse models, respectively, to show that other signalling factors, Bmp2 and Tbx2, are restricted to the AVC region by Notch signalling during development.

Furthermore, Watanabe and colleagues (2006) showed that deletion of Notch targets increases Bmp2 expression and expansion of the AVC tissue, however other, non-Notch restrictive factors involved in AVC development are likely to exist.[15]

Heart Valve Development

In order for the heart valve to properly form in the embryo, endocardial to mesenchymal transformation (EMT) must occur. The Notch pathway, alongside Wnt and Bmp, has been found to regulate the process of EMT, defects in which can lead to congenital heart valve disease. Interestingly, Timmerman and colleagues (2004) demonstrated that this role of Notch may also promote oncogenic transformation. This team also showed that embryos exhibited abortive endocardial EMT if they were deficient in Notch signalling components in vivo and in vitro. [16]

A more recent paper by Wang and colleagues (2013) further explored the underlying signalling processes and interrelationships of molecules that impact EMT. They found that Jagged1-Notch1 signalling in cells of the endocardium potentiates expression of Wnt4, which in turn carries out paracrine action on adjacent AVC tissue to upregulate Bmp2 expression and thus signal EMT. [17]

Trabeculation

Trabeculation is the initial process of ventricular chamber development that forms a series of cardiomyocyte projections within the lumens of the ventricles of the heart (called trabeculae). Grego-Bessa and colleagues (2007) addressed the roles Notch plays in trabeculation through RBPJk (the gene product of which interacts with Notch) and Notch1 gene manipulation. Mutants of these two genes showed perturbed expression and signalling of EphrinB2, NRG1 and BMP10, alongside reduced proliferation of myocardiocytes. This research ultimately suggested that EphrinB2 is a direct target of Notch in the endocardium that simultaneously requires the Notch-dependent action of BMP10 and NRG1 in order for ventricular myocardium proliferation and differentiation to occur normally. [18] Furthermore, the important process of trabeculation has recently been shown to be controlled by sequential Notch activation by an investigation by D’Amato and colleagues (2015). [19]

Development of the Outflow Tract

TBC

Central Nervous System

Simplified Diagram of Roles of Notch in Neuronal Differentiation
Simplified Diagram of Roles of Notch in Neuronal Differentiation. Notch influences the differentiation of embryonic stem cells into neural cells via signalling with RBP, cyclin D1 and Hes1. (This student-drawn image is based upon Figure 1 from Chuang, Tung and Lin's 2015 review: Neural differentiation from embryonic stem cells in vitro: An overview of the signaling pathways[20])

Early Neural Differentiation

Notch plays a major role in promoting neural commitment of cells. Lowell and colleagues (2011) used genetic manipulation to discover that the phenotype of stem cells is not affected by constitutively activated Notch in mouse embryonic stem cells (mESCs), however, interfering with Notch signalling -for example by pharmacological means- did impede neural fate determination. This role required Notch signalling via fibroblast growth factor (FGF) receptors. Furthermore, the conservation of the Notch signalling pathway within pluripotent stem cells is implied due to the existence of Notch ligands in stromal cells in human embryonic stem cells (hESCs) that induce neural differentiation. [21]

Das and colleagues (2010) manipulated Notch protein levels during specific stages of neural differentiation and found that if Notch signalling pathways were activated during day 3 of neural development for 6 hours, cell proliferation was dramatically enhanced. This was attributed to the induction by Notch of cyclin D1 expression. Without Notch signalling during neural development, there was reduced cyclin D1 levels. Manipulation of mESCs to express a dominant negative form of cyclin D1 resulted in abrogation of cell proliferation stimulated by Notch. Overall these results imply a temporally-specific role for Notch in CNS development, and that it requires cyclin D1 as a signalling molecule.[22]

pgh about RBP

pgh about Hes1 (use new paper as well)

Other Systems

The Pancreas

Many studies have shown that Notch also plays a significant role in the specification, cell proliferation, differentiation and plasticity of the pancreas [23].

The Endocrine System

TBC

Summary Table of Examples of Notch Signalling in Developmental Processes[6]

Organ/Tissue Processes regulated by Notch
Brain Controls the balance between gliogenesis and neurogenesis; stem cell maintenance
Craniofacial structures Palate morphogenesis: loss of Notch signalling results in cleft palate, fusion of the tongue with the palatal shelves, and other craniofacial defects; also involved in tooth development
Ear Defines the presumptive sensory epithelium; determines hair cell and supporting cell fates
Esophagus Regulates esophageal epithelial homeostasis
Heart Cardiac patterning, cardiomyocyte differentiation, valve development, ventricular trabeculation, outflow tract development
Intestine Controls proliferation and differentiation, including absorptive vs. secretory cell fates
Limbs Apical ectodermal ridge (AER) formation and digit morphogenesis, especially regulation of apoptosis
Lungs Lateral inhibition between tracheal cells prevents extra cells from assuming the lead position during tracheal branching morphogenesis
Neural crest Controls patterning of neural crest precursors for the outflow tract region of the heart; regulates the transition from Schwann cell precursor to Schwann cell, controls Schwann cell proliferation and inhibits myelination; controls melanocyte stem cell maintenance
Pancreas Specifies endocrine cell differentiation through lateral inhibition: endocrine lineage cells inhibit endocrine differentiation of their neighboring cells; maintains pancreatic endocrine precursor cells, inhibits terminal acinar cell differentiation; controls pancreatic epithelium branching and bud size
Skin Regulates cell adhesion, control of proliferation, hair follicle or feather papillae differentiation and homeostasis
Thyroid Regulates the numbers of thyrocyte and C-cell progenitors and regulates differentiation and endocrine function of thyrocytes and C-cells
Vasculature Regulates arteriovenous specification and differentiation in endothelial cells and vascular smooth muscle cells; regulates blood vessel sprouting and branching

Quiz Your Notch-Knowledge on Embryonic Development!

Which of the following systems does Notch signalling play a significant role in during embryonic development?

  The cardiovascular system
  The central nervous system
  The endocrine system
  All of the above


Roles in Animal Development

The Notch signalling pathway doesn't just play a significant role in human development, but also affects events such as neurogenesis and myogenesis in some animals (thus why these animals are often used as models for human development in research!). Read below for information on some of these roles for Notch.

Drosophila melanogaster

(The Fly)

Unlike the four Notch paralogs in humans, only one Notch homolog is present in Drosophila.[5]

Both canonical and non-canonical Notch signalling are involved in the structural and physiological responses and functional plasticity of olfactory receptor neurons in reaction to prolonged odour exposure.[24][25] Research has also shown that Notch is crucial for the formation of longitudinal connections in the Drosophila CNS. Kuzina, Song, and Giniger (2011) created temperature-sensitive mutations of Notch genes that prevented the development of mature longitudinal axon tracts. Additionally, it was found that the Notch phenotype appears at the earliest stages of the development of longitudinal connections in the CNS by observing early stage 13 embryos.[26]

Caenorhabditis elegans

(The Worm)

The Notch pathway in C. elegans occurs throughout development in populations of equipotent cells for neuronal function in postmitotic differentiated neurons. In these postmitotic neurons, there is a specialised post-embryonic development stage knows as 'dauer'. The Notch pathway is activated when cell signalling downstream of the developmental decision enter dauer. The Notch receptor glp-1 and the ligand lag-2 are expressed in the dauer stage and aid in maintaining this stage. Another Notch receptor, lin-12, functions upstream of insulin signalling components to promote conditions for growth and enhance dauer recovery. [27]

Danio rerio

(The Zebrafish)

The expression of Notch in the myogenic region and apical ectodermal ridge (AER) of the developing zebrafish fin is similar to what has been observed in developing chicken and mouse limbs, which shows how highly conserved the role of Notch signalling is in the development of appendages in vertebrates. During zebrafish embryogenesis, the timing and positioning of fin formation are dependent on Notch signalling. Notch is also involved in the actual processes of fin formation, such as AER signalling, chondrogenic differentiation, and myogenesis. In zebrafish embryos with defective Notch signalling, it was observed that the skeletal muscle fibres were thin and fragmented and the structure of the sarcomeres was significantly compromised.[28]

Summary of Functions of Proteins Involved in Notch Signalling[29]

Mammals Drosophila C.elegans Function
Notch 1-4 Notch Lin-12, Glp-1 Single transmembrane receptor and transcription factor
Delta 1, Delta3-4, Jagged1-2 Delta, Serrate APX-1, LAG-2, ARG-1, DSL-1 Single transmembrane ligands of the Notch receptor
CBF1/RBPJK
Mastermind1-3
Su(H)
Mastermind
Lag-1
Lag-3
DNA-binding transcription factor
Transcriptional co-activator
Lunatic, manic, and radical Fringe Fringe Modifies both Notch and its ligands
ADAM10, ADAM17 Kuzbanian, Kuzbanian-like, TACE SUP-17, ADM-4 Metalloproteases targeting S2 Notch cleavage sites
Presenilin 1-2, nicastrin, APH1, PEN2 Presenilin, nicastrin, APH1, PEN2 SEL-12, APH-1, APH-2, PEN2 Proteins of the γ-secretase complex, which targets Notch S3 and S4 cleavage sites
Mind bomb, skeletrophin, neuralized 1-2 Mind bomb 1-2, neuralized Y47D3A.22 E3 ubiquitin-protein ligases that targets Delta and Jagged/Serrate and regulate their endocytosis

Abnormalities in Notch signalling

Mutations in Notch genes and hence defects in Notch signalling have been implicated in the pathogenesis of several inherited diseases in humans.[30]

Disease Gene Phenotype
Alagille syndrome (OMIM118450, OMIM610205) JAG1, NOTCH2 Developmental abnormalities of the heart, liver, eye, and skeleton. Neonatal jaundice and cholestasis are early symptoms.
CADASIL syndrome (OMIM125310) NOTCH3 Autosomal vasuclar disorders linked to ischemic strokes, dementia, and premature death.
T-cell acute lymphoblastic leukaemia (OMIM613065) NOTCH1 (mutation in heterodimerasation domain or PEST domain) Tumour derived from T-cell progenitors. Symptoms include anaemia and enlargement of lymph nodes in the liver and/or spleen.
Spondylocostal dysostosis (OMIM122600) DLL3, Lunatic fringe Vertebral segmentation defects as well as rib abnormalities.

Additionally, Notch has been shown to be involved in cancer development and can act as both an oncogene and a tumour supressor gene.[30]

Gene Role of Notch Disease
NOTCH1
NOTCH2
Oncogene
Tumour suppressor
Pancreatic ductal adenocarcinoma
NCSTN
MAML1
APH1A
NOTCH2
Tumour suppressor Chronic myelomonocytic leukaemia
NOTCH1 Oncogene Chronic lymphocytic leukaemia
Activated NOTCH Tumour suppressor Hepatocellular carcinoma
NOTCH1
NOTCH2
NOTCH3
Tumour suppressor Head and neck squamous cell carcinoma
NOTCH Tumour suppressor B-cell acute lymphoblastic leukaemia
NOTCH1 Oncogene Non-small-cell lung cancer
NOTCH1 Oncogene T-cell acute lymphoblastic leukaemia

Alagille Syndrome

Alagille syndrome (AGS) is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. Diagnostic characteristics of the disease include liver disease, cardiac disease, vertebral defects, eye conditions, and facial features, as well as renal and vascular abnormalities.[31] In 94% of clinically diagnosed cases, a mutation in the gene encoding the Notch ligand JAG1 has been identified as a contributing factor. In combination with this, a mutation in the NOTCH2 gene has also been implicated in the manifestation of AGS in some patients.[32]

Spondylocostal Dysostosis

Spondylocostal Dysostosis (SD) is a collective term for conditions characterised by anomalies relating to rib and spine. The vertebrae are fused and shaped abnormally which can result in scoliosis. Similarly, the ribs may also be fused together or in some cases completely missing. As a result, people with this condition have short trunk dwarfism where their bodies are short in stature but have normal length limbs. Genetic changes are known to cause SD. SD Type 1 is the most prevalent form of this disease which is caused by the mutation in the delta like canonical Notch ligand 3 (DLL3 gene).[33] DLL3 provides the information for making a protein that regulates the Notch signalling pathway. The DLL3 protein in conjunction with the Notch pathway is primarily responsible for preventing the fusion of future vertebrae in a process known as somite segmentation.[34] An interruption in the Notch pathway inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine as seen in SD. 25 percent of SD arise from mutations in the identified genes and further research suggest that other genes involved in the Notch signalling pathway may also be related to SD.

Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)

CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life. The symptoms, age of onset, and prognosis are variable. Distinguishing symptoms include subcortical ischemic events (60-80% of cases), cognitive impairment (60% of late stage disease), migraines (30-40%), mood disturbances (30%), and apathy (40%).[35][36] Approximately 5-10% of CADASIL patients also experience seizures. The mean age of onset is 45 years of age and the disease duration is between 10–40 years. More than 95% of CADASIL cases present with pathogenic mutations in NOTCH3 (located on chromosome 19p13), specifically the epidermal growth factor-like repeat domain.[36][37] The NOTCH3 gene is involved in the normal development of blood vessels in both fetal and adult brains. In adults, NOTCH3 is expressed in the smooth muscle cells of arteries.[35] There is currently no effective treatment available for CADASIL.

Congenital Heart Defects

Aortic Valve Disease

Calcification of the aortic valve is a leading cause of adult heart disease. Mutations in NOTCH1 have been found to cause various aortic valve abnormalities, including the development of a bicuspid aortic valve (as opposed to tricuspid) and valve calcification.

A study by Garg et al. (2005) looked at mouse embryos and the expression of Notch1 during development. It was found that during normal embryonic development, Notch1 was abundantly expressed in the outflow tract mesenchyme (which develops into the heart valves) and the endocardium, as well as in the endothelial layer and mesenchyme of the aortic valve leaflets at the time of arterial trunk septation. Abnormal Notch1 led to the death of mice from vascular endothelial defects. Garg et al. then investigated whether NOTCH1 was involved in calcium deposition and therefore valve calcification. This is thought to be due to differentiation of valve cells into osteoblast-like cells. This leads to the upregulation of osteopontin, osteocalcin, and other osteoblast-specific genes, which is normally regulated by the transcription factor Runx2. Runx2 is known to be upregulated in animal models of valve calcification. Garg et al. found that Notch1 was capable of repressing Runx2 activation. Heart tissue and vasculature are normally abundant with the hairy-related transcriptional repressors Hrt1 and Hrt2 (also called Hey1 and Hey2), which are normally activated by Notch and are key mediators of the Notch pathway. Hrt1 and Hrt2 were both expressed in the endothelium of the mice aortic valve leaflets, the endocardium, and the vascular endothelium. They were found to inhibit the activation of osteoblast-specific genes by Runx2. It was thought that Hrt proteins can repress Runx2 by physical interaction as well as mediate Notch1 repression of Runx2. Therefore, a defect in Notch will cause upregulation of Runx2, due to the lack of repressor activity by Notch itself and the activation of the repressors Hrt1 and Hrt2. This leads to the expression of osteoblast genes that results in the differentiation of valvular cells into osteoblast-like cells and ultimately causes aortic valve calficiation.[38]

T-Cell Acute Lymphoblastic Leukaemia

T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive childhood cancer of the immune system's T-cells. The NOTCH1 gene encodes the Notch receptor that is involved in the determination of pluripotent cell progenitors to T-cells and the organisation of these cells in the developing thymus. Activating mutations in the extracellular domain and/or the C-terminal PEST domain of NOTCH1 have been identified in more than half of all cases of T-ALL.[39]

Current Areas of Research


Want to Read More About Notch?

Notch influences adult development as well!

Interestingly, Notch does not only play a role in human embryonic development, but has also been found to influence developmental processes in the after birth. One of these processes is neurogenesis, for example. Here are some links to interesting reviews about Notch in adult neural cell development (you may need your library log-in for access to full articles!):

TBC

links to interesting articles

Glossary

Cardiogenic From cardiogenesis - TBC
Cardiomyocyte TBC
Congenital TBC
Cyclin D1 TBC
Endocardial From endocardium - TBC
Gastrulation Describes the formative process of the formation of the trilaminar embryo containing the three germ layers.[1]
Haematopoietic From haematopoiesis - TBC
Mef2C promoters TBC
Mesenchymal From mesenchyme - TBC
Myogenic From myogenesis - meaning formation of muscle.[1]
Myogenin TBC
Neurogenic From neurogenesis - meaning the formation of nervous tissue.[1]
Oncogenic From oncogenesis - TBC
Paracrine TBC
Stromal cells TBC

References

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  2. 2.0 2.1 <pubmed>10075488</pubmed>
  3. 3.0 3.1 <pubmed>19255248</pubmed>
  4. <pubmed>27404588</pubmed>
  5. 5.0 5.1 5.2 5.3 5.4 Yamamoto, S., Schulze, K.L. & Bellen, H.J. (2014). Introduction to Notch Signalling. Notch Signaling: Methods and Protocols. Methods in Molecular Biology: 1187
  6. 6.0 6.1 <pubmed>21828089</pubmed>
  7. 7.0 7.1 <pubmed>18832173</pubmed>
  8. <pubmed>19580804</pubmed>
  9. <pubmed>10934030</pubmed>
  10. <pubmed>16690879</pubmed>
  11. <pubmed>19917614</pubmed>
  12. <pubmed>24345875</pubmed>
  13. <pubmed>17021042</pubmed>
  14. <pubmed>17259303</pubmed>
  15. <pubmed>16554359</pubmed>
  16. <pubmed>14701881</pubmed>
  17. <pubmed>23560082</pubmed>
  18. <pubmed>17336907</pubmed>
  19. <pubmed>26641715</pubmed>
  20. 25815127</pubmed>
  21. <pubmed>16594731</pubmed>
  22. <pubmed>20887720</pubmed>
  23. <pubmed>26729103</pubmed>
  24. <pubmed>26986723</pubmed>
  25. <pubmed>26011623</pubmed>
  26. <pubmed>21447553</pubmed>
  27. <pubmed>18599512</pubmed>
  28. <pubmed>23840804</pubmed>
  29. <pubmed>17761886</pubmed>
  30. 30.0 30.1 <pubmed>23729744</pubmed>
  31. <pubmed>26548814</pubmed>
  32. <pubmed>16773578</pubmed>
  33. <pubmed>10742114</pubmed>
  34. <pubmed>11236715</pubmed>
  35. 35.0 35.1 <pubmed>21045164</pubmed>
  36. 36.0 36.1 <pubmed>20301673</pubmed>
  37. <pubmed>24579972</pubmed>
  38. <pubmed>16025100</pubmed>
  39. <pubmed>15472075</pubmed>