UNC-5 is a

receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...

for

netrin Netrins are a class of proteins involved in axon guidance. They are named after the Sanskrit word "netr", which means "one who guides". Netrins are genetically conserved across nematode worms, fruit flies, frogs, mice, and humans. Structurally, ...

s including UNC-6. 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 ...

. UNC-5 uses repulsion to direct axons while the other netrin receptor UNC-40 attracts axons to the source of netrin production.

Discovery of netrins

The term

was first used in a study done in 1990 in

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 ...

and was called UNC-6. Studies performed on rodents in 1994 have determined that netrins are vital to guidance cues. The vertebrate orthologue of UNC-6, netrin-1 was determined to be a key guidance cue for axons moving toward the ventral midline in the rodent embryo spinal cord. Netrin-1 has been identified as a critical component of

embryonic development 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 ...

with functions in axon guidance, cell migration, morphogenesis and angiogenesis. The most recent studies have found that there are 5 types of netrins expressed in animals. Ectotopic expression of UNC-5 can result in short or long range repulsion.

Axon guidance

The guidance of axons to their targets in the developing

nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...

is believed to involve

diffusible Passive transport is a type of membrane transport that does not require energy to move substances across cell membranes. Instead of using cellular energy, like active transport, passive transport relies on the second law of thermodynamics to dri ...

chemotropic factors

secreted 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical ...

by target cells. Floor plate cells at the ventral midline of the spinal cord secrete a diffusible factor or factors that promotes the outgrowth of spinal

commissural A commissure () is the location at which two objects abut or are joined. The term is used especially in the fields of anatomy and biology. * The most common usage of the term refers to the brain's commissures, of which there are five. Such a commi ...

axons and attracts these axons

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

. Recent studies indicate that several axon guidance mechanisms are highly conserved in all animals, whereas others, though still conserved in a general sense, show strong

evolutionary Evolution is change in the heredity, heritable Phenotypic trait, characteristics of biological populations over successive generations. These characteristics are the Gene expression, expressions of genes, which are passed on from parent to ...

divergence In vector calculus, divergence is a vector operator that operates on a vector field, producing a scalar field giving the quantity of the vector field's source at each point. More technically, the divergence represents the volume density of the ...

at a detailed mechanistic level. Expression of UNC-6

and its receptor UNC-5 is required for guiding pioneering axons and migrating cells in

C. 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'' (r ...

Netrin Netrins are a class of proteins involved in axon guidance. They are named after the Sanskrit word "netr", which means "one who guides". Netrins are genetically conserved across nematode worms, fruit flies, frogs, mice, and humans. Structurally, ...

s are

molecule A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

s that transmit their activity through 2 different receptors. The function of UNC-5 is to repel axons while the other receptor UNC-40 (or

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''. ...

) attracts axons to the source of UNC-6 production. Methods such as

antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

staining, transgene expression and microarray analysis have confirmed that UNC-5 is expressed in DA9 motor neurons. Eight pairs of chemosensory neurons in

take up fluorescein dyes entering through the chemosensory organs. When filled with dye, the processes and cell bodies of these neurons can be examined in live animals by fluorescence microscopy. Using this technique five genes were identified: unc-33, unc-44, unc-51, unc-76, and unc-106. These genes we found to affect the growth of the amphid and phasmid axons in mutants.

Cell migration

There are three

phase Phase or phases may refer to: Science *State of matter, or phase, one of the distinct forms in which matter can exist *Phase (matter), a region of space throughout which all physical properties are essentially uniform * Phase space, a mathematic ...

s in hermaphrodite distal tip

cell migration Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular dire ...

which are distinguished by the

orientation Orientation may refer to: Positioning in physical space * Map orientation, the relationship between directions on a map and compass directions * Orientation (housing), the position of a building with respect to the sun, a concept in building de ...

of their movements which alternate between anteroposterior and

dorsoventral Standard anatomical terms of location are used to unambiguously describe the anatomy of animals, including humans. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position prov ...

axes. Experimentation has shown that UNC-5 is coincident with the second migration phase and that premature expression will result in turning in a UNC-6 dependent manner. This also demonstrates the mechanism that regulates UNC-5 is critical for UNC-6 netrin guidance cue responsiveness. Although it normally guides axons along the

axis, UNC-40 can be co-opted with SAX-3 to affect cell migrations along the anterior posterior axis. VAB-8 protein is identified as an upstream regulator for UNC-40 and identifies the mechanism for

polarity Polarity may refer to: Science *Electrical polarity, direction of electrical current *Polarity (mutual inductance), the relationship between components such as transformer windings * Polarity (projective geometry), in mathematics, a duality of ord ...

in axon and cell migration.

Formation

Growth

An experiment was performed to determine if UNC-5 is required for

localization Localization or localisation may refer to: Biology * Localization of function, locating psychological functions in the brain or nervous system; see Linguistic intelligence * Localization of sensation, ability to tell what part of the body is a ...

of presynaptic components in DA9. When testing the effect of unc-5::intron::unc-5 transgene on a mislocalization defect in UNC-5 mutant animals at 25 °C a significant rescue of the mislocalization defect was observed. In mutant animals, ventral and dorsal migrations are disrupted but

longitudinal Longitudinal is a geometric term of location which may refer to: * Longitude ** Line of longitude, also called a meridian * Longitudinal engine, an internal combustion engine in which the crankshaft is oriented along the long axis of the vehicle, ...

movements are unaffected. They discovered that this rescue does not occur at 16 °C because the transgene fails to produce UNC-5 at that temperature. This is relevant because is shows that the mislocalization defect is due to a change in temperature at the L4

larva A larva (; plural larvae ) is a distinct juvenile form many animals undergo before metamorphosis into adults. Animals with indirect development such as insects, amphibians, or cnidarians typically have a larval phase of their life cycle. The ...

l stage which occurs after DA9 is fully developed. This suggests that UNC-5 is only required for the early outgrowth phase to guide axons. UNC-5 presents a novel function in maintaining polarized localization of GFP::RAB-3 independently of early polarization and guidance. When testing directly for whether UNC-6 netrin provides information for localization of presynaptic components an interesting discovery was made. The egl-20::unc-6 transgene creates an enlarged asynaptic zone of the DA9 dorsal axon. They further observed that the enlarged asynaptic

domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined **Domain of definition of a partial function **Natural domain of a partial function **Domain of holomorphy of a function * Do ...

is restored partly in UNC-5 which demonstrates that UNC-5 acts cell autonomously in DA9 in order to mediate ectopic UNC-6 exclusion of presynaptic components. The UNC-6 gradient is high ventrally and low dorsally and encompasses the

dendrite Dendrites (from Greek δένδρον ''déndron'', "tree"), also dendrons, are branched protoplasmic extensions of a nerve cell that propagate the electrochemical stimulation received from other neural cells to the cell body, or soma, of the n ...

and ventral axon of DA9. UNC-6 was recently found to cause the initial polarization of the

hermaphrodite specific neuronal

cell body The soma (pl. ''somata'' or ''somas''), perikaryon (pl. ''perikarya''), neurocyton, or cell body is the bulbous, non-process portion of a neuron or other brain cell type, containing the cell nucleus. The word 'soma' comes from the Greek '' σῶμ ...

. The findings of this experiment suggest that UNC-6 and UNC-5 coordinate two different functions in DA9 and that the netrin is expressed after axon guidance is complete. Extracellular cues such as Wnt

fibroblast A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...

growth factor can promote

synapse 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 ...

formation, contradicting the traditional view of

formation from contact between synaptic partners to trigger the assembly of synaptic components.

Inhibitor Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...

y factors such as UNC-5 play essential roles in the formation and maintenance of synaptic components. Axon Hillock

Adult expression

In a study done in rat

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...

s, increased netrin-1, UNC-5 homologue levels were observed compared to lower levels measured in the

embryo 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 spe ...

. From this study multiple

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

transcripts were detected by northern blot analysis. This finding suggests that

s could be encoded by alternatively spliced mRNAs. During

only one

splice Splice may refer to: Connections * Rope splicing, joining two pieces of rope or cable by weaving the strands of each into the other ** Eye splice, a method of creating a permanent loop in the end of multi stranded rope by means of rope splicing * ...

variant Variant may refer to: In arts and entertainment * ''Variant'' (magazine), a former British cultural magazine * Variant cover, an issue of comic books with varying cover art * ''Variant'' (novel), a novel by Robison Wells * " The Variant", 2021 e ...

is detected while there are two in the adult model. The results of these findings suggest that UNC-5 homologues make up a primary method of netrin-1 signal transduction in the adult

. This shows that netrin-1 plays a major role in the adult brain and has the potential for

therapeutic A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis. As a rule, each therapy has indications and contraindications. There are many different ...

applications.

Plasticity

Similar to growth cone guidance,

formation is cued by UNC-5 through a UNC-6 gradient that repels the dorsal axon migration. Dendritic

filopodia Filopodia (singular filopodium) are slender cytoplasmic projections that extend beyond the leading edge of lamellipodia in migrating cells. Within the lamellipodium, actin ribs are known as ''microspikes'', and when they extend beyond the lame ...

extend from the

dendritic Dendrite derives from the Greek word "dendron" meaning ( "tree-like"), and may refer to: Biology *Dendrite, a branched projection of a neuron *Dendrite (non-neuronal), branching projections of certain skin cells and immune cells Physical * Dendr ...

shaft during synaptogenesis and appear as though they are reaching out for a presynaptic axon. Despite the appearance of attaching to an axon, cell signaling is still required for complete synaptic formation. An experiment was performed to determine the role of UNC-5 in axonal growth after spinal cord injury. The

is expressed by

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

s in the corticospinal and rubrospinal projections, and by intrinsic

s of the

both before and after the injury. When testing

UNC-5

bodies are taken from the

to neutralize netrin-1 in myelin. This increases the neurite outgrowth from UNC-5 expressing spinal motor neurons.

UNC-129

UNC-129 is a

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...

in the transforming growth factor family in

which encodes transforming growth factor β (TGF-β). Like UNC-6 it guides pioneer axons along the

axis of C. elegans. TGF-β is expressed only in dorsal rows of body wall muscles and not ventral. Ectotopic expression of UNC-129 from the muscle results in disrupted growth cone and cell migrations. This shows that UNC-129 is responsible for mediating expression of

required for

. Recent findings have shown that UNC-129 is also responsible for long range repulsive guidance of UNC-6. This mechanism enhances UNC-40 signaling while inhibiting UNC-5 alone. This causes an increase in sensitivity in

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 growth ...

to UNC-6 as they travel up the UNC-129 gradient. UNC-129 mediates expression of

polarity information required for axon guidance and guided cell migrations in

Dendritic self avoidance

Recently it was found that

s do not overlap and actively avoid each other because cell specific membrane

s trigger mutual repulsion. In the absence of UNC-6 signaling however, dendrites failed to repel each other. This finding supports the idea that UNC-6 is critical for axon and

guidance in the developmental stage. It is also known that self avoidance requires UNC-6 but not a UNC-6 graded signal. A ventral to dorsal UNC-6

gradient In vector calculus, the gradient of a scalar-valued differentiable function of several variables is the vector field (or vector-valued function) \nabla f whose value at a point p is the "direction and rate of fastest increase". If the gradi ...

is not required for expression and dendritic self avoidance is independent of such a

. UNC-6 that binds to UNC-40 takes on different properties and functions as a short range guidance cue.

Vertebrate laminins

Netrins share the same

terminal Terminal may refer to: Computing Hardware * Terminal (electronics), a device for joining electrical circuits together * Terminal (telecommunication), a device communicating over a line * Computer terminal, a set of primary input and output devic ...

structure with

vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...

laminins Laminins are a protein family, 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 organ ...

but appear minimally related. 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 ...

assembly across species, Vertebrate laminin-1 (α1β1γ1) and laminin-10 (α5β1γ1), like the two

laminins, are

nically expressed and are essential for basement membrane assembly. During the basement assembly process

anchor to the cell surface through their G domains after

polymer A polymer (; Greek '' poly-'', "many" + ''-mer'', "part") is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic a ...

izing through their LN domains. Netrins are involved in heterotropic LN domain interactions during this process which suggests that although similar in structure, the functions of the two families are different.

Applications

Tumorigenesis

Netrin-1 and its

s DCC and UNC-5 show a new mechanism for

induction Induction, Inducible or Inductive may refer to: Biology and medicine * Labor induction (birth/pregnancy) * Induction chemotherapy, in medicine * Induced stem cells, stem cells derived from somatic, reproductive, pluripotent or other cell t ...

or suppression

regulation Regulation is the management of complex systems according to a set of rules and trends. In systems theory, these types of rules exist in various fields of biology and society, but the term has slightly different meanings according to context. For ...

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 ...

. Evidence shows that this signaling pathway in humans is frequently inactivated. During the last 15 years, controversial data has failed to firmly establish whether DCC is indeed a

tumour A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

suppressor

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. However, the recent observations that DCC triggers cell death and is a receptor for netrin-1, a

recently implicated in

colorectal The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being ...

tumorigenesis. The established role of DCC and netrin-1 during organization of the

could be viewed as a further challenge to the position that DCC inactivation might play a significant role in tumorigenesis. Recent observations on DCC's functions in intracellular

signaling In signal processing, a signal is a function that conveys information about a phenomenon. Any quantity that can vary over space or time can be used as a signal to share messages between observers. The ''IEEE Transactions on Signal Processing'' ...

have renewed interest in the potential contribution of DCC inactivation to

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

. Data shows that, when engaged by

ligands, DCC may activate downstream signaling pathways and in settings where netrin is absent or at low levels, DCC can promote

. The binding of netrin-1 to its

s inhibits the

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

suppressor p53 dependent

. Such

s share the property of inducing

in the absence of

, hence creating a cellular state of dependence on the

. Thus, netrin-1 may not only be a chemotropic factor for

s but also a survival factor. This discovery shows that netrin-1 receptor pathways play an important role in tumorigenesis.

Schwann cells

A study was performed to determine the effect of

-1 on

schwann cell Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensh ...

proliferation Proliferation may refer to: Weapons *Nuclear proliferation, the spread of nuclear weapons, material, and technology *Chemical weapon proliferation, the spread of chemical weapons, material, and technology * Small arms proliferation, the spread of ...

. Unc5b is the sole

expressed in RT4 schwannoma cells and adult primary Schwann cells, and netrin-1 and Unc5b are found to be expressed in the injured

sciatic nerve The sciatic nerve, also called the ischiadic nerve, is a large nerve in humans and other vertebrate animals which is the largest branch of the sacral plexus and runs alongside the hip joint and down the lower limb. It is the longest and widest si ...

. It was also found that the

-1-induced

Schwann cell Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensh ...

was blocked by the specific

inhibition Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...

of Unc5b expression with RNAi. These data suggests that netrin-1 could be an

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, es ...

trophic factor for

s in the injured

peripheral A peripheral or peripheral device is an auxiliary device used to put information into and get information out of a computer. The term ''peripheral device'' refers to all hardware components that are attached to a computer and are controlled by the ...

nerve A nerve is an enclosed, cable-like bundle of nerve fibers (called axons) in the peripheral nervous system. A nerve transmits electrical impulses. It is the basic unit of the peripheral nervous system. A nerve provides a common pathway for the e ...