Netrins are a class of

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

s involved in

axon guidance Axon guidance (also called axon pathfinding) is a subfield of neural development concerning the process by which neurons send out axons to reach their correct targets. Axons often follow very precise paths in the nervous system, and how they mana ...

. They are named after the

Sanskrit Sanskrit (; attributively , ; nominally , , ) is a classical language belonging to the Indo-Aryan branch of the Indo-European languages. It arose in South Asia after its predecessor languages had diffused there from the northwest in the late ...

word "netr", which means "one who guides". Netrins are genetically conserved across nematode worms,

fruit flies Fruit fly may refer to: Organisms * Drosophilidae, a family of small flies, including: ** ''Drosophila'', the genus of small fruit flies and vinegar flies ** ''Drosophila melanogaster'' or common fruit fly ** ''Drosophila suzukii'' or Asian fruit ...

frogs A frog is any member of a diverse and largely carnivorous group of short-bodied, tailless amphibians composing the order Anura (ανοὐρά, literally ''without tail'' in Ancient Greek). The oldest fossil "proto-frog" ''Triadobatrachus'' is ...

mice A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

, and

humans Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...

. Structurally, netrin resembles the extracellular matrix protein

laminin Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina (one of the layers of the basement membrane), the protein network foundation for most cells and organs. The laminins ...

. Netrins are chemotropic; a growing

axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action po ...

will either move towards or away from a higher concentration of netrin. Though the detailed mechanism of

is not fully understood, it is known that netrin attraction is mediated through

UNC-40/DCC Netrin receptor DCC, also known as DCC, or colorectal cancer suppressor is a protein which in humans is encoded by the ''DCC'' gene. DCC has long been implicated in colorectal cancer and its previous name was ''Deleted in colorectal carcinoma''. ...

cell surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral m ...

s and repulsion is mediated through

UNC-5 UNC-5 is a receptor for netrins including UNC-6. Netrins are a class of proteins involved in axon guidance. UNC-5 uses repulsion to direct axons while the other netrin receptor UNC-40 attracts axons to the source of netrin production. Discove ...

receptors. Netrins also act as

growth factors A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...

, encouraging cell growth activities in target cells. Mice deficient in netrin fail to form the

hippocampal comissure The fornix (from lat, fornix, lit=arch) is a C-shaped bundle of nerve fibers in the brain that acts as the major output tract of the hippocampus. The fornix also carries some afferent fibers to the hippocampus from structures in the diencephalon a ...

or the

corpus callosum The corpus callosum (Latin for "tough body"), also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental mam ...

. A proposed

model A model is an informative representation of an object, person or system. The term originally denoted the plans of a building in late 16th-century English, and derived via French and Italian ultimately from Latin ''modulus'', a measure. Models c ...

for netrin activity in the

spinal column The vertebral column, also known as the backbone or spine, is part of the axial skeleton. The vertebral column is the defining characteristic of a vertebrate in which the notochord (a flexible rod of uniform composition) found in all chordates ...

of developing human

embryos An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sper ...

is that netrins are released by the

floor plate The floor plate is a structure integral to the developing nervous system of vertebrate organisms. Located on the ventral midline of the embryonic neural tube, the floor plate is a specialized glial structure that spans the anteroposterior axis f ...

and then are picked up by receptor proteins embedded in the

growth cones Growth may refer to: Biology * Auxology, the study of all aspects of human physical growth * Bacterial growth * Cell growth * Growth hormone, a peptide hormone that stimulates growth * Human development (biology) * Plant growth * Secondary grow ...

of axons belonging to neurons in the developing spinal column. The bodies of these neurons remain stationary while the axons follow a path defined by netrins, eventually connecting to neurons inside the embryonic brain by developing

synapses In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...

. Research supports that new axons tend to follow previously traced pathways, rather than being guided by netrins or related chemotropic factors.

Discovery

Netrin was first described in the nematode ''

Caenorhabditis elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (ro ...

'' in 1990, and named UNC-6, according to standard ''C. elegans'' naming protocol. The first mammalian homologue of UNC-6 was discovered in 1994, where it was discovered to be a vital guidance cue for rodent commissural axons in the spinal cord. As of 2009, five mammalian Netrins have been identified. Netrins 1, 3, and 4 are secreted proteins, whereas G1 and G2 are membrane bound proteins tethered by

Glycophosphatidylinositol Glycosylphosphatidylinositol (), or glycophosphatidylinositol, or GPI in short, is a phosphoglyceride that can be attached to the C-terminus of a protein during posttranslational modification. The resulting GPI-anchored proteins play key roles i ...

tails. All netrins discovered in

invertebrates Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordate ...

thus far are secreted.

Overview of netrins

The netrin family is composed mostly of secreted proteins which serve as bifunctional signals: attracting some neurons while repelling others during the development of the brain. Expressed in the midline of all animals possessing

bilateral symmetry Symmetry in biology refers to the symmetry observed in organisms, including plants, animals, fungi, and bacteria. External symmetry can be easily seen by just looking at an organism. For example, take the face of a human being which has a pla ...

, they can act as long or short range signals during

neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...

. In order to carry out their functions, netrins interact with specific receptors: DCC or

, depending on whether they are trying to attract or repel neurons, respectively. There is a high degree of conservation in the secondary structure of netrins, which has several domains which are homologous with laminin at the amino terminal end. The C-terminal domain is where most of the variation is found between species and contains different amino acids which allow interaction with specific proteins in extracellular matrix or on the cell surface. The differences in terms of structure and function have led to the identifications of several different types of netrins including netrin-1, netrin-3, and netrins-G.

Key netrins

Netrin-1 Netrin-1 is a protein that in humans is encoded by the ''NTN1'' gene. Netrin is included in a family of laminin-related secreted proteins. The function of this gene has not yet been defined; however, netrin is thought to be involved in axon gu ...

is found in the floor plate and

neuroepithelial cells Neuroepithelial cells, or neuroectodermal cells, form the wall of the closed neural tube in early embryonic development. The neuroepithelial cells span the thickness of the tube's wall, connecting with the pial surface and with the ventricular or ...

of the ventral region of the spinal cord, as well as other locations in the nervous system including the somatic mesoderm, pancreas and cardiac muscle. Its main role is in axonal guidance,

neuronal migration The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The fiel ...

and

morphogenesis Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of devel ...

of different branching structures. Mice with mutations in the netrin-1 gene were observed to be lacking in forebrain and spinal cord commissural axons. Netrin-1 and -3 has been described to have an exclusive expression in cancer cells. Netrin-3 is different from other netrins. While expressed during development of the peripheral nervous system in the motor, sensory and sympathetic neurons, it is very limited in the central nervous system. Studies with netrin-3 have noticed a reduced ability to bind with DCC when compared with netrin-1. This suggests that it mainly operates through other receptors. Netrins-G are secreted but remain bound to the extracellular surface of the cell membrane through

(GPI). They are expressed predominantly in the central nervous system in places such as the

thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...

and mitral cells of the

olfactory bulb The olfactory bulb (Latin: ''bulbus olfactorius'') is a grey matter, neural structure of the vertebrate forebrain involved in olfaction, the sense of odor, smell. It sends olfactory information to be further processed in the amygdala, the orbitof ...

. They do not bind to DCC or UNC-5 and instead bind to ligand NGL-1, which results in an intracellular transduction cascade. The two versions, netrin-G1 and netrin-G2, are found only in vertebrates. It is believed that they evolved independently of other netrins in order to facilitate the construction of the brain.

Netrin receptors

DCC and

proteins mediate netrin-1 responses. The UNC-5 protein is mainly involved in signaling repulsion. DCC, which is implicated in attraction, can also serve as a co-factor in repulsion signaling when far away from the source of netrin-1. DCC is highly expressed in the central nervous system and associated with the

basal lamina The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often incorrectly referred to as the basement membrane, though it does constitute a portion of the basement membrane. The ba ...

of epithelial cells. In the absence of netrin-1, these receptors are known to induce

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

Axonal guidance

Growth cones Growth may refer to: Biology * Auxology, the study of all aspects of human physical growth * Bacterial growth * Cell growth * Growth hormone, a peptide hormone that stimulates growth * Human development (biology) * Plant growth * Secondary grow ...

that are located at the end of developing axons during embryogenesis are responsible for the elongation of the axon during

migration Migration, migratory, or migrate may refer to: Human migration * Human migration, physical movement by humans from one region to another ** International migration, when peoples cross state boundaries and stay in the host state for some minimum le ...

. Elongation occurs in response to both tropic and atropic factors present in the surrounding environment. Netrins are one such tropic factor secreted by axonal target cells that function as a crucial axonal guidance protein in both vertebrate and invertebrate organisms. Studies in multiple organisms including, mice, rats, chicks, the nematode ''Caenorhabditis elegans'', the fruit fly ''

Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly" or "pomace fly". Starting with Ch ...

'' and the zebrafish ''

Danio rerio The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ...

'' have indicated that secreted netrins are bifunctional, meaning that they can act as either attractants or repellants in directing axonal extension. In addition, many studies have characterized netrins as both short and long range cues, acting in the immediate or distant vicinity of their source cell (the axonal target cell).

Attraction

Studies of

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

(CNS) development in chick and rodent models have identified the netrin-1 protein as a particularly important vertebrate axonal guidance cue. Most significantly, it was observed that the specialized cells of the

located at the ventral midline of the embryonic brain secrete netrin-1, which resulted in a protein gradient. This gradient is most concentrated at the ventral midline and becomes increasingly diffuse as you move dorsally. Additional research in netrin deficient mice found that when netrin associates with the

Deleted in Colorectal Cancer Netrin receptor DCC, also known as DCC, or colorectal cancer suppressor is a protein which in humans is encoded by the ''DCC'' gene. DCC has long been implicated in colorectal cancer and its previous name was ''Deleted in colorectal carcinoma''. ...

(DCC) receptor on the axonal growth cone an attractant response is initiated. This was further supported by an observed absence of ventral commissure (i.e.

) development in mice lacking either netrin-1 or DCC. Similar results were observed in experiments with the netrin-1 homolog UNC-6 discovered in ''C. elegans'' The same early expression and formation of a protein concentration gradient emanating from the ventral midline is observed in epidermal cells of the developing worm. Evidence suggests that this gradient is essential for the long-range function of UNC-6 in guiding the initial circumferential migration of axons to the ventral midline and that the UNC-40 receptor mediates the attractive response. As additional axons reach the midline, the temporal and spatial expression of UNC-6 becomes increasing restricted, indicating that after a more general dorsal-ventral guidance of axons, UNC-6 is further involved in directing axons to more specific locations. Recently, scientists have characterized many of the cellular mechanisms by which netrin-1 binding to DCC motivates axonal attraction through at least three independent signaling pathways. In all three pathways netrin-1 is observed to cause the

homodimerization In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...

of DCC that begins the chemoattraction cascade. In the first pathway, the focal adhesion kinase (FAK) is bound to DCC and both undergo tyrosine phosphorylation upon netrin-1 binding that induces the recruitment and phosphorylation of Src and

Fyn Funen ( da, Fyn, ), with an area of , is the third-largest island of Denmark, after Zealand and Vendsyssel-Thy. It is the 165th-largest island in the world. It is located in the central part of the country and has a population of 469,947 as ...

, which is hypothesized to lead to an increase in second messengers Rac1 and Cdc42 thereby promoting growth cone extension. In a second possible pathway, phosphatidylinositol transfer protein α (PITP) binds to phosphorylated DCC which induces phospholipase C (PLC) to increase the ratio of

cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...

to cGMP. This increase of cAMP relative to cGMP activates L-type Ca²⁺ channels as well as transient receptor potential channels (TRPC's) causing an influx of extracellular Ca²⁺. Evidence suggests that this increased calcium is responsible for the activation of Rho GTPases, Cdc42 Rac1 and the nuclear transcription factor

NFAT Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the developme ...

which can all initiate growth cone extension. Additional studies have also shown that netrin-induced signaling between DCC downstream targets NcK, and

Wiskott–Aldrich syndrome Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia). It is also sometimes called the eczem ...

protein WASP trigger Rac1 and Cdc42 and subsequently axonal growth.

Repulsion

Both DCC in vertebrates and UNC-40 in ''C. elegans'' have been shown to initiate a repulsive rather than attractive response when associated with the netrin receptor Unc5. In the same ventral midline gradient discussed above, netrin-1 acts as a chemorepellant for axons of the trochlear motor neurons, thus directing their growth dorsally (away from the ventral midline). Antibody inhibition of DCC in embryonic ''

Xenopus ''Xenopus'' () (Gk., ξενος, ''xenos''=strange, πους, ''pous''=foot, commonly known as the clawed frog) is a genus of highly aquatic frogs native to sub-Saharan Africa. Twenty species are currently described within it. The two best-known ...

'' spinal cord inhibited both attraction and repulsion in vitro. Likewise, multiple defects were observed in ''C. elegans'' unc-40 mutants; however, errors in migration patterns were more profoundly affected by mutations in the unc-5 gene, indicating that binding of the netrin-1 homologue UNC-6 to the UNC-5 receptor alone can repel axonal growth. In both vertebrate and invertebrate systems, short range

chemorepulsion Chemorepulsion is the directional movement of a cell away from a substance. Of the two directional varieties of chemotaxis, chemoattraction has been studied to a much greater extent. Only recently have the key components of the chemorepulsive pathw ...

in which the concentration of netrins is high, seems to primarily occur via the UNC-5 receptor, while long range repulsive effects at more diffuse concentrations require coordination between DCC (UNC-40 in ''C.elegans'') and UNC-5. It is currently hypothesized that long range chemorepulsion involves initiation of the

Arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...

pathway upon netrin-1 interaction with the DCC/UNC-5 complex. This pathway increases the intracellular levels of 12-HPETE (12-Hydroperoxy-5, 8, 10, 14-Eicosatetraenoic Acid), which induces cGMP signaling and subsequently causes a decrease in the cAMP/cGMP ratio. Reducing this ratio inhibits calcium conductance through the

L-type calcium channels The L-type calcium channel (also known as the dihydropyridine channel, or DHP channel) is part of the high-voltage activated family of voltage-dependent calcium channel. "L" stands for long-lasting referring to the length of activation. This c ...

(LCC) and ultimately results in growth cone repulsion though a possible activation of Ras homolog gene family, member A (RhoA). A similar RhoA-mediated mechanism is proposed for short range chemorepulsion whereby netrin-1 binding to UNC-5 homodimers alone induces tyrosine phosphorylation requiring FAK and Src, which as a result activates RhoA. An additional mechanism proposes that binding of the tyrosine phosphatase

Shp2 Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in huma ...

to the netrin-1/UNC-5 complex may also trigger chemorepulsion through RhoA.

Glial and mesodermal guidance

Many studies have shown that

netrin-1 Netrin-1 is a protein that in humans is encoded by the ''NTN1'' gene. Netrin is included in a family of laminin-related secreted proteins. The function of this gene has not yet been defined; however, netrin is thought to be involved in axon gu ...

, UNC-40, UNC-6, and UNC-5 are involved in the migration of

glia Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form mye ...

during

embryogenesis An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...

. During the migratory phase in ''Drosophila melanogaster'', embryonic peripheral glia (ePG) express UNC-5. In UNC-5 knockout organisms, ePG either stall while migrating or fail to migrate. UNC-6 signaling in ''C. elegans'', coupled with the UNC-40 receptor on neurons, promotes

synaptogenesis Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenes ...

and assembles the glial endfeet around the synapse.

Functions outside of neuronal guidance

Although originally understood to be specifically involved in axonal guidance in the central nervous system, new research has linked netrin to cancer regulation, the development and formation of non-neural tissue, and the detection of cancer and other diseases.

Development and regulation of tissue

Netrin has been discovered to play a key role in the development and mature regulation of tissue outside the nervous system. Some of the non-neural tissues implicated include lung, placental, vasculature, pancreas, muscle and mammary gland tissue. Netrin contributes to tissue

by controlling developing cell migration and cell adhesion in different organs. In developing mammary glands, the growing tips of the ductal network consist of two layers made up of luminal epithelial cells and cap cells. The luminal cells secrete netrin 1, which binds to the receptor neogenin (a homologue of DCC) on the cap cells. This allows for adhesion between the two cell layers, which is necessary for the proper morphogenesis of the terminal end buds (TEBs) in the mammary glands. Loss of the gene coding for either netrin 1 or neogenin leads to the improper formation of the (TEBs), suggesting that rather than acting as a guidance molecule as in neuronal systems, netrin 1 serves as an adhesive in mammary tissue. During the morphogenesis of the embryonic lung,

epithelial cells Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

express netrin 1 and netrin 4. These netrins surround

endoderm Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gast ...

buds in the

basement membrane The basement membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between Epithelium, epithelial tissues including mesot ...

, preventing distal tip cells from expressing DCC and UNC5B. This allows for normal development of the lung and halts potentially dangerous over-branching and budding from occurring. In

pancreatic development The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an endocr ...

, netrin 1 is expressed in epithelial ductal cells and localizes to the basal membrane. Netrin 1 associates with several elements in the

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...

, including

collagen IV Collagen IV (ColIV or Col4) is a type of collagen found primarily in the basal lamina. The collagen IV C4 domain at the C-terminus is not removed in post-translational processing, and the fibers link head-to-head, rather than in parallel. Also, ...

fibronectin Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...

, and integral proteins α6β4 and α3β1. These elements in the extracellular matrix are responsible for epithelial cell adhesion and migration, suggesting that netrin 1 is associated with the guidance of epithelial cells in the embryonic pancreas. Netrin has been implicated as a vital molecule for the proliferation of vascular networks. Multiple studies have found different effects of netrin on these branching vessels. The endothelial tip cells in vascular tissue display similar properties to the growth cone found in neuronal tissue. Studies have discovered that these same endothelial tip cells also express UNC5B, which netrin 1 can bind to, inhibiting

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...

. In contrast, several studies show that netrin-1 actually promotes blood vessel branching. In conjunction with this research, it has been found that netrin 4 is responsible for growth in the lymphatic vascular system. Overall, these studies show that regulating effects of netrin is dependent on the type of vascular tissue. Recently, netrin has been implicated in angiogenesis in the placenta, making it vital to the survival of the fetus. This finding has implications in the future treatment of vascular disease in the placenta. In adults, netrin has been implicated in the regulation of

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...

movement and inflammation. Netrin 1 has been found to inhibit leukocyte migration to inflamed areas in the body. This provides evidence that the up regulation of netrin protects injured tissue from excess inflammation. Also, the migration of adult neural progenitor cell and adult spinal cord progenitor cells to the spine is netrin 1 dependent. Little is known of the mechanism controlling the inhibition or attraction of these stem cells.

Cancer regulation and disease markers

In various human cancers, it has been shown that netrin becomes over-expressed. It has also been shown that certain receptors become down-regulated in this process. The netrin receptors DCC and UNC5H are responsible for apoptotic regulation. The absence of netrin 1 is responsible for apoptosis, while the presence of netrin 1 leads to an inhibition of the

apoptotic pathway Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes inclu ...

. This pathway is unique and independent of the mitochondrial and

death receptor The tumor necrosis factor receptor superfamily (TNFRSF) is a protein superfamily of cytokine receptors characterized by the ability to bind tumor necrosis factors (TNFs) via an extracellular cysteine-rich domain. With the exception of nerve growt ...

pathways that lead to controlled cell death. This has been observed in the human colon epithelium, where higher levels of natural cell death at the upper portion of the villi correlated with a smaller gradient of netrin-1. This linked the role of netrin with tissue death and growth. Tumor suppressor

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

is responsible for the expression of netrin-1, implying that netrin may be the pathway through which p53 regulates the

cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...

. Because netrin is so influential in the regulation of cell death, the gene which codes for netrin (''NTN1'') is considered to be an

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

. Because netrin-1 has been found to be upregulated in tumors, recent research has attempted to identify netrin-1 as a

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

for the onset of cancer in the human body. It was found that netrin can be found at above-normal levels in the blood plasma of patients who are positive for renal, liver, prostate, meningioma of brain, pituitary adenoma, glioblastoma and breast cancer. Netrin-3 appears to be specifically expressed in Neublastoma (a paediatric tumour) and in small cell lung cancer (SCLC) where it correlates with a bad patient prognosis.

Continued research on netrin

There are still many unanswered questions regarding the netrin family of molecules. It is still uncertain what role vertebrate homologues of UNC-5 play in

. Although much is known about the expression of netrin during development, little is yet known about its regulation in later development in the brain. Netrin knockout mice show that there is much to learn about the many roles of netrin in axonal guidance. Another important line of current research targets netrin as a treatment for various diseases, including cancer,

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...

, and

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

. In avian and mouse model organisms suffering from

neuroblastoma Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in the ...

, interfering with the netrin-1 autocrine loop in malignant tumors leads to cell death. This could lead to possible alternative therapies resulting from future trials. Similar treatments regarding the down-regulation of netrin-1 are also being investigated for metastatic breast and colorectal cancers. Recent studies also suggest that netrin is involved in a cardioprotective role by releasing NO gas. In mice, netrin has also been associated with the regulation of (Aβ) peptide, which is responsible for

amyloid plaques Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of micr ...

in Alzheimer's disease.

References

* *{{cite book , title=The Science Times Book of the Brain , url=https://archive.org/details/sciencetimesbook00wade , url-access=registration , year=1998 , editor1-first=Nicholas , editor1-last=Wade , publisher=The Lyons Press, isbn=9781558216532 Developmental neuroscience