2012 Group 4 Project

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Notch 2 Protein.

Notch Signaling

Introduction

Drosophila fly with notched wings. Student drawn image.

The notch signaling pathway is a highly evolutionary cell signaling system which participates in multiple cellular functions during development and adulthood in all metazoan animals. [1] The name of the pathway itself was adopted from Thomas Hunt Morgan's discovery as he noticed notches in the wings of the Drosophilia melanogaster, initiating the start to further research in why this was the case. In the process of development and regeneration, the notch pathway is active in its involvement in cell to cell communication, tissue regeneration, maintaining homeostasis, cell fate specification and differentiation of cells. As it is a highly regulated and important pathway particularly in the stages of growth, a slight mutation or dysfunction in its course may cause developmental defects or diseases in the adult as the Notch Signaling Pathway review informs. [2] This network consists of five transmembrane proteins in the form of ligands from the Jagged and Delta families (Jagged1, Jagged2, Delta1, Delta3 and Delta4) which targets the notch receptor to activate the pathway. Mammals possess four different notch receptors named Notch1, Notch2, Notch3 and Notch4 which are activated and bound to the membrane by these five ligands. [3] As notch signaling is a highly important pathway significant in many regulatory functions, the occurrence of a mutation or an inappropriate activation of the pathway will result in the development of diseases and cancers. This project will highlight the important functions and roles of notch signaling in specific organs such as the central nervous system, cardiovascular development, pancreatic and kidney development and the current research being done for further discovery in the field of notch signaling.


History

Year Description
1917 Thomas Hunt Morgan discovered the notch locus when noticing a strain of Drosophila melanogaster had notches in their wingblades [4].

Also identified the scientific potential for the Drosophila model as he discovered how rapid the development was as well as being inexpensive, simple and of high fecundity. [5]

1920 T. Morgan and his students identified many Notch alleles by this time and as these began to accumulate, a lot of new information was added to the study of the Notch pathway. Often genetic patterns which were hard to interpret were found and after many interpretations it was suggested that the best way to represent the Notch locus would be in a genetic map in a spiral configuration. [6]
Early 1930s Don Poulson conducted work for his doctoral thesis and studied the embryonic phenotypes that were involved in deletion of chromosomes. However at the time, the relationship between embryonic development and genes were in high doubt of having no relevance of each other.

Poulson also discovered the alleles of a gene that was related to the phenotype of notched wings in the fruit fly. [5]

1950s and 1960s Bill Welshons, his colleague and wife Jean Welshons from Iowa studied the genetics and cytology of the 3C7 section of the X chromosome which holds the Notch. Here the most detailed and informative genetic analysis was undertaken of the Notch locus and an accurate genetic map was produced. [7] [8]
1970s The findings of the Notch76b8 inversion locus, which had a breakpoint in one locus and another in its adjacent region, enabled the discovery of the recognising the ability of genes to jump over the repetitive regions and thus allowed for cloning of the breakpoint within the Notch locus to start. This was the beginning of the identification of Notch as a fundamental receptor in development and regeneration. [9]
1978 Homeotic genes described in Drosophila by Lewis. [10]
1980 Christiane Nüsslein-Volhard and Eric Wieschaus discovered the Hh gene in Drosophila and identified fifteen segmentation genes in the search for mutations affecting the segmental pattern related to number and polarity. Also found that the development of Drosophila was dependent on the sequences of activities of three particular genes: maternal genes, segmentation genes, homeotic genes. [5]
1990 Identification of the interacting loci - "Delta" and "mastermind" which belong to the group of neurogenic loci, in searching for genes whose products may have an interaction with the Notch protein. It was identified that the mutations in these two loci affect early neurogenesis. Discovered that the lesions of the Notch alleles nd and nd2 interacting with mastermind mutations are involved in the intracellular changes in the domain of the Notch protein. [11]
1995 Don Poulson's previously investigated link between the actions of a genetic locus, Notch and embryonic morphogenesis was granted as the 'fly Nobel Prize'. [5]
2002 Following recent research, it was suggested that the aspartyl-beta-hydroxylation may be involved in another post-translational modification of epidermal growth factor domains which can modify parts of the Notch signaling pathway. [12]
2012 The Jag1 Notch ligand was expressed in PA6 cells and was found that the Notch signaling inhibition pathway blocked the ability for differentiation to occur in PA6 cells. [13]

Pathway

Notch Signaling Pathway [14]

Notch proteins present in vertebrates (Notch1, Notch4) are non-reusable receptors that are transported to the plasma membrane as cleaved polypeptides. At the membrane, they are activated by Delta and Serrate families of membrane bound ligands which results in two additional proteolytic cleavages. They in turn release the Notch Intracellular Domain (NICD) from the plasma membrane. The Notch Intracellular Domain is then transported to the nucleus where it "forms a complex with the DNA binding protein CSL, displacing a histone deacetylase (HDAc)-co-repressor (CoR) complex from CSL." From here, the NICD-CSL complex engages with components of an activation complexes (MAML1, HATs) leading to transcriptional activation of Notch target genes. [3]

In other words, the bipartite notch receptor protein spans the cell membrane with both an intracellular and extracellular component. A ligand protein binds with the extracellular component thereby cleaving the notch receptor. As a result of proteolysis, the intracellular component of the notch protein (Notch intra) is liberated and can enter the nucleus to engage other DNA-binding proteins and regulate gene expression (ie, converting transcription factor CBF1/CSL from a gene repressor to a gene activator).

See video under External links for further understanding.



Proteins and Receptors

There are three major players in the Notch Signalling Pathway; the delta ligand, notch receptor and the DNA-binding CSL. The binding of the delta ligand of one cell to the notch receptor of another cell results in two proteolytic cleavages of the Notch receptor. The internal portion of the Notch receptor (Notch Intracellular Domain or Notch intra)then translocates to the nucleus where it interacts with the DNA-binding CSL molecule, releasing the co-repressor complex and recruiting a co-activating complex (which includes the translocated Notch Intracellular Domain). This in turn initiates Notch target gene activation.


Table 1. Major Components of Notch Signalling in Vertebrates.

Major Components of Notch Pathway Description Image of Component Relationship to Pathway Various Members of Component
Notch Receptor
  • transmembrane receptors
  • non-reusable (single-pass)
  • extracellular arrays of epidermal growth factor (EGF) repeats (mediating direct contact between Notch and ligand)
  • therefore must be adjacent to ligand
Notch Receptor. Student drawn image.
Once Notch receptor has been cleaved, Notch (Intra) translocates to the nucleus where it activates CSL
  • Notch 1
  • Notch 2
  • Notch 3
  • Notch 4
Delta-type Ligand
  • single-pass
  • transmembrane proteins
  • extracellular arrays of epidermal growth factor (EGF) repeats (mediating direct contact between Notch and ligand)
  • and therefore must be adjacent to the notch expressing cell for signaling to occur
Delta-type Ligand. Student drawn image.


Ligand triggers 2 different cleavages (known as S2 and S3) which releases the Notch Intracellular Domain; Notch Intra)
  • Delta
  • Serrate (known as Jagged in Mammals)
CSL transcription factor protein
  • sequence-specific DNA-binding proteins
  • function downstream of Notch
  • Notch (intra) activates CSL
CSL Transcription Factor. Student drawn image.
At a resting state, CSL usually associates with a co-repressor complex which actively represses the transcription of Notch target genes. When the cleaved Notch Intra activates CSL, a co-activator complex (including Notch Intra) replaces the co-repressor complex, enabling the mediation of Notch target gene activation

Adapted from '''Notch signaling: a simple pathway becomes complex'''[15]


As explained above, Notch resides at the cell surface as a single-pass transmembrane receptor. It is then activated and makes its way to the nucleus where it acts as a transcription factor. The notch receptor displays "temporal as well as spacial versatility, acting as a strong developmental signal, controlling cell fate determination and lineage commitment, and playing a pivotal role in embryonic and adult stem cell proliferation and differentiation" [16]. Its versatile function and widespread nature allows for potential interactions with an array of signaling and binding partners.

The remaining notch-pathway components and auxiliary factors involved within the Drosophila Melanogaster and Vertebrates and Mammals


Table 2. Minor Components and auxiliary factors of Notch Pathway Signalling

Components of Notch Pathway Drosophila Melanogaster Vertebrates and Mammals
Receptor Notch Notch1, Notch2, Notch3, Notch4
Ligand Delta, Serrate Delta1, Delta2, Delta3, Delta4, Serrate, Jagged1, Jagged2
CSL transcription factor protein Su(H) CBF1/RBPkJ
Co-Activator Mastermind Mastermind1, Mastermind2, Mastermind3
Co-Repressor Hairless, SMRTR SMRT
γ-secretase complex Presenilin, nicastrin, APH1, PEN2 Presenilin1, Presenilin2, nicastrin, APH1, PEN2
Glycosyl transferase Fringe Lunatic Fringe, Radical Fringe, Manic Fringe
Metalloprotease, receptor cleavage Kuzbanian, Tace CG7908 ADAM10, TACE/ADAM17
Metalloprotease, receptor cleavage Kuzbanian-like
Ring finger E3 (ligand regulation) Mind bomb1 Mind bomb1, Mind bomb2
Ring finger E3 (ligand regulation) Neuralized Neuralized1, Neuralized2
Ring finger E3 (receptor regulation) Deltex Deltex
HECT domain E3 (receptor regulation)) Su(dx), NEDD4 Itch, NEDD4
F-box E3 (nuclear) Archipelago FBW7/SEL10
Numb, cytoplasmic Notch inhibitor Numb Numb, Numb-like
Numb-associated kinase Numb associated Kinase AP2-associated kinase
4-pass transmembrane protein, positive regulator Sanpodo
Immunoglobulin C2-type cell-adhesion molecule Echinoid
bHLH repessors, target genes E(spl)bHLH HES/ESR/HEY
Neuralized E3 inhibitors Bearded, Tom, M4

Adapted from '''Notch signaling: a simple pathway becomes complex'''[15]

(Where there is a space is where a specific protein has not yet been identified.)

Normal Function of Notch

Notch signaling pathway plays a vital role in metazoan development. Notch protein activates a signaling pathway that controls the expression of genes that are responsible for cell division, growth, migration and apoptosis. Utilization of the Notch signaling pathway determines the fate of cells in the embryonic phase. As cells begin to divide in the developmental stages, they utilize the Notch receptor protein which magnifies and combines the “molecular differences between adjacent cells”[17]. That is, Notch provides a scaffold in the embryo that guides cells to follow a certain pattern in accordance with its neighbouring cells. The correct Notch signaling pathway is important in the development of organisms as incorrect expression or mutations in the pathway can lead the progression of tumours.

The importance of Notch signaling pathway can further be explored in the developmental stages of Central Nervous System in Vertebrates, Cardiovascular Development, Pancreas Development and Kidney Development.

Role of Notch in the development of Central Nervous System

Role of Notch in the development of CNS - Student drawn image.

The development of the central nervous system (CNS) in vertebrates results in the separation of primitive neuroepithelium into two main roots, neurons and glia. Neurons originate in embryonic life from multipotent progenitors near the ventricle. They are then transferred to their desired endpoint where they “integrate into the brain circuitry”[18]. In terms of glia cells, they are produced in the subventricular zone during “late embryonic and early postnatal stages”[18]. This can be further explored in the image 'Role of Notch in the Development of CNS'.

Notch in Cardiovascular Development

The cardiovascular organ is one of the first systems to develop where all the Notch receptors and ligands participate in the formation of the cardiac layers required in vertebrate embryogenesis as mentioned in the review of Notch Signaling and Cardiac Repair. [16] The heart evolves from the cardiogenic mesoderm to form the double-walled primary heart tube. This takes place when blood islands are organised in the yolk sac of the embryo from the formation of hemangioblastic cells. These cells further differentiate into hematopoietic and angioblastic cells. The hematopoietic cells are responsible for producing blood cells and vascular endothelial cells (ECs) are generated from angioblastic cells[19]. In the process of forming new blood vessels, smooth muscle cells and pericytes work together to synthesis various sizes of vessels. Large amount of Notch signaling is conducted through transactivation. This is done by ligand-expressing cell (the signaling cell) stimulating its neighbouring receptor-expressing cell (the receiving cell). In studies conducted on mouse embryos that lacked Notch receptor[19] Notch 1 led to heart defects,[16] as the Notch 1 receptor was found to be expressed in cardiac stem cells. Thus further highlighting the importance of Notch 1 in cardiomyogenesis.


Notch in Pancreatic Development

Spheroid pancreatic cancer stem cells

The pancreas is derived from the endoderm and are formed from three main branches, the acinar cells responsible for producing digestive enzymes, the islets of Langerhans (α-and β-endocrine cells) regulates blood-glucose level through hormones such as insulin and glucagon and finally the ductal tree which attaches the pancreas to the duodenum. The behaviour of Notch in the development of the pancreas is not well defined. Therefore the role of the members of Notch signaling, Notch 1, Notch 2 and Rbpi were further tested. In vivo studies,Rbpj and combined Notch1/Notch2 knockout mice using Ptf1a+/Cre(ex1) mice were crossed with floxed Rbpj or Notch1/Notch2 mice [20]. The mice were examined at various stages of their embryonic development for the formation of exocrine and endocrine pancreatic progression. The study revealed that the lack of Rbpi in pancreatic progenitor cells delayed the development of exocrine pancreas up to embryonic day 18.5 and resulted in premature differentiation of endocrine pancreas cells. Hence the role of Rbpi is essential in the early developmental stages but not necessarily important in the later phases[20]. Subsequently the absence of Notch1 and Notch2 only distressed the proliferation of the pancreatic epithelial cells in the early stages and did not cause the inhibition of pancreatic development[20]. Furthermore unlike Rbpi, Notch1 and Notch2 are not crucial for the development of the pancreas.


Notch in Kidney Development

Developing Kidney.

The development of human kidney begins with a segmentation process in which nephrons mold into an S-shape body [21]. Each region of the S-shaped body is responsible for the formation of nephron components, such as the lower segment differentiates into podocytes, the middle region forms proximal epithelial cells and the upper region of the S-shaped body gives rise to the ascending limb of the loop of Henle and distal convoluted tubule[21]. Notch plays an essential role in the developmental stages of the nephron. This was established by the expression of Notch1 in the potential mesangium, distal tubule and collecting ducts of during nephrogenesis[22].Notch2 was also expressed in the primitive proximal tubule with very limited co-localization with podocyte progenitors. Notch ligand, Jagged1 revealed limited expression in primary vesicles, comma-shaped bodies, and S-shaped bodies and later in developing distal tubules and the prospective loop of Henle[21].

Abnormal Function of Notch

Notch in Schizophrenia

Schizophrenia is the most severe form of mental disorders in developed countries with incidences occurring in 15.2/100,000 persons. [23] Schizophrenia is amongst the top ten illnesses that cause turmoil within society in regards to disease according to a survey conducted by the World Health Organization[24]. It rigorously affects the thought process of the mind via psychotic incidences that disrupt ones ability to reside in mainstream society. It is a mental disorder that produces such symptoms as hallucination, delusion, psychological episodes as well the inability to make rational decisions, which causes grief amongst the patient and their family. The aetiology of schizophrenia is obscured due to numerous hypotheses proposed throughout the decades that have prevailed in the acceptance of a single cause of schizophrenia. [25] Genetic architecture and environmental factors are two of the most well recognized theories that are believed to cause schizophrenia. Current technological improvements in molecular genetics have allowed scientists to associate genetics with schizophrenia through adoption and twin studies. Statistical analysis of monozygotic and dizygotic twins suggests 81% (95% confidence interval, 73%-90%) was due to heritability linkage whereas 11% is associated to environmental factors. [26] Genetic studies have postulated that there is a link between Notch 4 gene and schizophrenia. [27], [28], [29] This may be due to the recent findings that allude to the susceptibility locus located on chromosome 6p during early developmental stages. [30] Specific mutations in a CTG repeat site in exon 1 of Notch 4 gene revealed that majority of the 210 candidates in a study [31], performed poorly in the Wisconsin CardSort Test (WCST). WCST is used to determine the functionality of the frontal lobe as well as measuring the integrity of those diagnosed with schizophrenia. The performance of the subjects in the study [31]may be due to inadequate development of brain matter and neural stem cell development during embryonic stages. Hence early inconsistency in neurogenesis may be linked with Notch4 gene [32]mutations however further research into epidemiology factors as well as in vivo models may conclude a definite link between Notch4 gene and schizophrenia.

Notch in Melanoma

Malignant Melanoma vs Neavus.

Melanoma is a relatively common neoplasm that is anatomically incident at various sites including the skin, oral and anogenital mucosal surfaces, oesophagus, meninges and uvea. Due to public health campaigning, raising awareness of the early signs of melanoma, most lesions are recognised early allowing for prompt excision and a bright prognosis. [33] Statistics indicate incidence of melanoma worldwide is increasing. It is unclear whether actual incidence is rising or diagnostic practises are merely improving [34] The genetic setting in which melanoma oncogenesis occurs is broad and variable. Polymorphisms involving particular genes have been linked to incidence. Those associated with MC1R (Melanocortin-1-receptor), ASIP (Agouti signaling protein) and TYR (Tyrosinase) as well as Notch correlate with phenotypes associated with increased risk. These include red and blonde hair colours, and lightly pigmented and freckling skin tones. It should be noted that these represent only a small increase in risk. [35]

Cutaneous melanoma originates from the highly dendritic melanocytes of the stratum basale, which are interspersed between dividing epidermal stem cells and maturing keratinocytes. Development is divided into two stages, the radial growth phase and the vertical growth phase. Radial growth is the period of horizontal expansion involving the epidermis and superficial dermis when melanoma cells lack the capacity to metastasise or invade significantly. After a variably long period, the melanoma shifts into its vertical growth phase (VGP), where tumour cells progress into the subjacent dermis. [33]

Recent study [36] demonstrates the importance of Notch1 in the development of melanoma and regression of the tumour. Notch1 plays a crucial role in in the vertical growth phase of primary melanoma cells. Condensed expression of active Notch1 in serum-independant and growth-factor independent VGA melanoma cell lines demonstrated significant increase in proliferative manner similar to metastatic melanoma. Evidence in growth of cell colony on agar as well as “xenograft growth in SCID mice” [36]was also prevalent in the study. Activated Notch1 is moderately regulated through MAPK and PI3k/AKT pathways. Another gene of interest is PTEN (Phosphatase and tensin homologue), a tumour-suppressor gene that down regulates PI-3K/AKT (Phosphoinositide-3-kinase/Protein-Kinase-B) signaling. This pathway is often associated with increased cellular survival and augmented capacity for invasion. Epigenetic silencing of PTEN (perhaps by hypermethylation) is associated with 20% of sporadic melanomas. [33] It is important to note that mutations that augment the RAS, PI-3K/AKT pathways are required for the pathogenesis of melanoma hence highlighting the importance of Notch1 in the development of melanoma.

Current Research

The knowledge of Notch signaling is currently well understood. In almost all aforementioned diseases, Notch plays an important role in the development and differentiation of cells due to its proto-oncogene function. Some aspects, however, in regards to its role in diseases are somewhat perforated. Significance of pin-pointing certain location of Notch ligand and its receptor on a particular tumour cell can lead to avenues of research. This may be achieved by developing better real time imaging in vivo animal models.

In the case of melanoma, the prognosis associated with metastatic melanoma is dreary and there are no effective therapies. Future treatment targets have been identified as including the RAS and PI-3K/AKT pathways. As Notch1 is partially interplayed with the PI-3K/AKT pathway, it may be wise to explore the reasoning behind Notch target genes. There are notions of immunotherapeutic treatments that will ‘train’ cytotoxic lymphocytes to recognise and destroy melanoma cells [33] . Ultimately, these aspects may form part of the framework of personalised cancer therapies.

Also, it is speculated that Alzheimer's disease is due to the cleavage of amyloid precursor protein (APP) by gamma-secretase which gives rise to a toxic amyloid beta-peptide. The secretions cause neurodegenaraton observed in the disease [37]. Notch 1 homologues as well as Notch ligands Delta and Jagged are substrates of gamma-secretase and are thought to be involved in the rise of neurotoxicity in the brain due to the inhibition of gamma-secretase. It is postulated that proteolysis of the Notch by gamma-secretase could lead to the neurodegeneation [37] in patients suffering from Alzheimer’s disease. Therefore research into the Notch signaling pathway in Alzheimer's disease could lead to better treatment and prognosis.

Multiple Sclerosis, an inflammatory demyelinating disease in which remyelination is limited; is a disease which affects the central nervous system and can, to varying degrees, interfere with the transmission of nerve impulses throughout the brain, spinal cord and optic nerves. The cause and cure still remain elusive, however, it has only recently been found that Jagged1 signaling inhibited process outgrowth from human oligodendrocytes. This is highly significant because Notch may, in the near future provide therapeutic intervention for this disease. [38]

Glossary

Apoptosis:The death of cells that occurs as a normal and controlled part of an organism's growth or development.

Bipartite: Consisting of two parts.

Cutaneous:Of, relating to, or affecting the skin.

Cytology: The study of cells

Demyelinating disease: Any disease of the nervous system in which the myelin sheath of neurons is damaged. This impairs the conduction of signals in the affected nerves, causing impairment in sensation, movement, cognition, or other functions depending on which nerves are involved.

Dendritic: Having a branched form resembling a tree.

Dizygotic:(of twins) Derived from two separate ova, fraternal

Drosophila melanogaster: A species of the family of flies in the family 'Drosophilidae', commonly known as the fruit fly.

Epidemiology: The branch of medicine that deals with the incidence, distribution, and possible control of diseases and other factors relating to health.

Endocrine:The process whereby one organ will secrete a molecule (e.g., a hormone) into the bloodstream or lymphatic system, that has an effect on another distant organ, in a different part of the body.

Exocrine:Secreting a chemical substance that is transported by a duct out to a particular region of the body.

Fecundity: Ability to reproduce.

Glia: The connective tissue of the nervous system, consisting of several different types of cell associated with neurons.

Hemangioblast: Hemangioblast is a multipotent cell, common precursor to hematopoietic and endothelial cells.

Homeotic genes: Genes which can cause mutations where one structure is replaced by another (eg: a leg replaced for a wing).

In vivo: (in experimentation) Using a whole, living organism as opposed to a dead, or partial organism

Keratinocytes: An epidermal cell that produces keratin.

Lymphocytes: A form of small leukocyte (white blood cell) with a single round nucleus, occurring esp. in the lymphatic system.

Melanocytes: A mature melanin-forming cell, typically in the skin.

Maternal Genes: Genes from the mother genome which are required for the early development of a normal embryo.

Mesangium: An inner layer of the glomerulus (a tiny ball-shaped structure composed of capillary blood vessels actively involved in the filtration of the blood to form urine) in the kidneys.

Mesoderm: The middle layer of an embryo in early development.

Metastatic: The spreading of a disease (especially cancer) to another part of the body.

Metazoan: Any animal of the subkingdom Metazoa; all animals except protozoans (unicellular eukaryotic organisms) and sponges.

Monozygotic: (of twins) Derived from a single ovum, and thus identical.

Nephron: Each of the functional units in the kidney, consisting of a glomerulus and its associated tubule, through which the glomerular filtrate passes before emerging as urine.

Neurogenesis: The process by which neurons are generated from neural and progenitor cells where it is responsible in the growth and development of nervous tissue in the brain.

Nucleus: The large, membrane-bounded organelle that contains the genetic material, in the form of multiple linear DNA molecules organized into structures called chromosomes.

Neurons: A specialized cell transmitting nerve impulses; a nerve cell.

Oligodendrocyte: A type of brain cell whose main functions are to provide support and to insulate the axons in the central nervous system of some vertebrates.

Pericyte: Also known as Rouget cell, a pericyte is an adventitial cell or mural cell that is found in the central nervous system which occurs in small blood vessels. It plays an important role in maintaining the blood-brain-barrier and in other homeostatic functions in the brain.

Podocyte: Podocytes (or visceral epithelial cells) are cells in the Bowman's capsule in the kidneys that wrap around the capillaries of the glomerulus.

Polymorphisms: The occurrence of a number of alternative forms within a section of a nucleic acid or protein molecule.

Polypeptide: A linear organic polymer consisting of a large number of amino-acid residues bonded together in a chain.

Proteolytic: Of or relating to proteolysis; the breakdown of proteins or peptides into amino acids by the action of enzymes.

Segmentation Genes: Any genes involved in the pattern formation in the early stages in the embryo; responsible for the formation of the body segments.

Subventricular Zone: The subventricular zone (SVZ) is a paired brain structure situated throughout the lateral walls of the lateral ventricles.

Stratum basale: The innermost layer of the epidermis.

Transactivation: Activation of a gene at one locus by the presence of a particular gene at another locus, typically following infection by a virus.

Ventricle:A chamber of the heart that receives blood from an atrium and pumps it to the arteries.

Uvea: The pigmented layer of the eye, lying beneath the sclera and cornea, and comprising the iris, choroid, and ciliary body.

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