UNC-5 is a

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

for netrins 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 residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

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

axon An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...

s while the other netrin receptor UNC-40 attracts axons to the source of netrin production.

Discovery of netrins

The term netrin 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 Hybrid word, blend of the Greek ''caeno-'' (recent), ''r ...

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 In developmental biology, animal embryonic development, also known as animal embryogenesis, is the developmental stage of an animal embryo. Embryonic development starts with the fertilization of an egg cell (ovum) by a sperm, sperm cell (spermat ...

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

s to their targets in the developing

nervous system In biology, the nervous system is the complex system, highly complex part of an animal that coordinates its behavior, actions and sense, sensory information by transmitting action potential, signals to and from different parts of its body. Th ...

is believed to involve diffusible chemotropic factors

secreted 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 mech ...

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 axons and attracts these

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

. 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 the change in the heritable characteristics of biological populations over successive generations. It occurs when evolutionary processes such as natural selection and genetic drift act on genetic variation, resulting in certa ...

divergence In vector calculus, divergence is a vector operator that operates on a vector field, producing a scalar field giving the rate that the vector field alters the volume in an infinitesimal neighborhood of each point. (In 2D this "volume" refers to ...

at a detailed mechanistic level. Expression of UNC-6 netrin 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'' ( ...

. Netrins are

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

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) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...

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 A fluorescence microscope is an optical microscope that uses fluorescence instead of, or in addition to, scattering, reflection, and attenuation or absorption, to study the properties of organic or inorganic substances. A fluorescence micro ...

. 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 mathematica ...

s in hermaphrodite distal tip

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

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 des ...

of their movements which alternate between

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

and dorsoventral 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 dorsoventral 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 in axon and cell

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 ...

Formation

Growth

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

presynaptic In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...

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

and

dorsal Dorsal (from Latin ''dorsum'' ‘back’) may refer to: * Dorsal (anatomy), an anatomical term of location referring to the back or upper side of an organism or parts of an organism * Dorsal, positioned on top of an aircraft's fuselage The fus ...

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 (; : larvae ) is a distinct juvenile form many animals undergo before metamorphosis into their next life stage. Animals with indirect development such as insects, some arachnids, amphibians, or cnidarians typically have a larval phase ...

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

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 A domain is a geographic area controlled by a single person or organization. Domain may also refer to: Law and human geography * Demesne, in English common law and other Medieval European contexts, lands directly managed by their holder rather ...

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

and encompasses the

dendrite A dendrite (from Ancient Greek language, Greek δένδρον ''déndron'', "tree") or dendron is a branched cytoplasmic process that extends from a nerve cell that propagates the neurotransmission, electrochemical stimulation received from oth ...

and

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

hermaphrodite specific neuronal

cell body In cellular neuroscience, the soma (: somata or somas; ), neurocyton, or cell body is the bulbous, non-process portion of a neuron or other brain cell type, containing the cell nucleus. Although it is often used to refer to neurons, it can also ...

. 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 typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...

growth factor can promote

synapse In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...

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: 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 neurotransmi ...

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 that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...

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

embryo An embryo ( ) is the initial stage of development for 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 sp ...

. 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 netrin

s could be encoded by alternatively spliced mRNAs. During

only one splice variant 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 is the attempted remediation of a health problem, usually following a medical diagnosis. Both words, ''treatment'' and ''therapy'', are often abbreviated tx, Tx, or Tx. As a rule, each therapy has indications an ...

applications.

Plasticity

Similar to growth cone guidance,

formation is cued by UNC-5 through a UNC-6 gradient that repels the

migration. Dendritic

filopodia Filopodia (: 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 lamellipod ...

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 *Dendri ...

shaft during synaptogenesis and appear as though they are reaching out for a

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 netrin is expressed by

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

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 A motor neuron (or motoneuron), also known as efferent neuron is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or ...

UNC-129

UNC-129 is a

ligand In coordination chemistry, a ligand is an ion or molecule with a 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 el ...

in the transforming growth factor family in

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

to UNC-6 as they travel up the UNC-129 gradient. UNC-129 mediates expression of dorsoventral 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 A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...

s trigger mutual repulsion. In the absence of UNC-6 signaling however,

dendrites A dendrite (from Greek δένδρον ''déndron'', "tree") or dendron is a branched cytoplasmic process that extends from a nerve cell that propagates the electrochemical stimulation received from other neural cells to the cell body, or soma ...

failed to repel each other. This finding supports the idea that UNC-6 is critical for axon and

guidance in the

developmental Development of the human body is the process of growth to maturity. The process begins with fertilization, where an egg released from the ovary of a female is penetrated by a sperm cell from a male. The resulting zygote develops through mitosis ...

stage. It is also known that self avoidance requires UNC-6 but not a UNC-6 graded signal. A

UNC-6

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

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 structure with

vertebrate Vertebrates () are animals with a vertebral column (backbone or spine), and a cranium, or skull. The vertebral column surrounds and protects the spinal cord, while the cranium protects the brain. The vertebrates make up the subphylum Vertebra ...

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

but appear minimally related. The

basement membrane The basement membrane, also known as base 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 epithelial tis ...

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 () is a chemical substance, substance or material that consists of very large molecules, or macromolecules, that are constituted by many repeat unit, repeating subunits derived from one or more species of monomers. Due to their br ...

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 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. Fo ...

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

. Evidence shows that this

signaling pathway In biology, cell signaling (cell signalling in British English) is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in both prokaryotes and eukary ...

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 (biology), 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 tiss ...

suppressor A silencer, also known as a sound suppressor, suppressor, or sound moderator, is a gun barrel#Muzzle, muzzle device that suppresses the muzzle blast, blast created when a gun (firearm or airgun) is discharged, thereby reducing the sound inten ...

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. However, the recent observations that DCC triggers

cell Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...

death and is a receptor for netrin-1, a

recently implicated in colorectal 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 This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

signaling A signal is both the process and the result of transmission of data over some media accomplished by embedding some variation. Signals are important in multiple subject fields including signal processing, information theory and biology. ...

have renewed interest in the potential contribution of DCC inactivation to

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

. Data shows that, when engaged by netrin 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 ...

p53 dependent

. Such

s share the property of inducing

in the absence of

, hence creating a

ular 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 netrin-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 glial cell, satellite ...

proliferation. Unc5b is the sole

expressed in RT4 schwannoma cells and adult primary

Schwann cells 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 glial cell, satellite ...

, 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. It is the largest branch of the sacral plexus and runs alongside the hip joint and down the right lower limb. It is the longest and widest ...

. It was also found that the netrin-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 glial cell, satellite ...

proliferation was blocked by the specific

inhibition Inhibitor or inhibition may refer to: 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 neurotransm ...

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

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

trophic factor for

s in the injured

peripheral A peripheral device, or simply peripheral, is an auxiliary hardware device that a computer uses to transfer information externally. A peripheral is a hardware component that is accessible to and controlled by a computer but is not a core compo ...

nerve A nerve is an enclosed, cable-like bundle of nerve fibers (called axons). Nerves have historically been considered the basic units of the peripheral nervous system. A nerve provides a common pathway for the Electrochemistry, electrochemical nerv ...