UNC-5

Netrin/DCC receptor
Netrin/DCC receptor
Identifiers
Symbol	Netrin/DCC receptor
Membranome	1137

Last updated November 29, 2023

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.^[1]

Discovery of netrins

The term netrin was first used in a study done in 1990 in Caenorhabditis elegans and was called UNC-6.^[2] 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 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.^[3]

Axon guidance

The guidance of axons to their targets in the developing nervous system is believed to involve diffusible chemotropic factors secreted 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 axons in vitro.^[4] 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 divergence 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.^[5] Netrins are axon guidance molecules 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) attracts axons to the source of UNC-6 production. Methods such as antibody staining, transgene expression and microarray analysis have confirmed that UNC-5 is expressed in DA9 motor neurons.^[1] Eight pairs of chemosensory neurons in Caenorhabditis elegans 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.^[2]

Cell migration

There are three phases in hermaphrodite distal tip cell migration in Caenorhabditis elegans which are distinguished by the orientation of their movements which alternate between anteroposterior 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.^[6] 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.^[7]

Formation

Growth

An experiment was performed to determine if UNC-5 is required for localization 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 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 larval 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.^[1] 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 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 and ventral axon of DA9. UNC-6 was recently found to cause the initial polarization of the C. elegans hermaphrodite specific neuronal cell body. 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 growth factor can promote synapse formation, contradicting the traditional view of synapse formation from contact between synaptic partners to trigger the assembly of synaptic components. Inhibitory factors such as UNC-5 play essential roles in the formation and maintenance of synaptic components.^[1]

Adult expression

In a study done in rat spinal cords, increased netrin-1, UNC-5 homologue levels were observed compared to lower levels measured in the embryo.^[8] From this study multiple mRNA transcripts were detected by northern blot analysis. This finding suggests that netrin receptors could be encoded by alternatively spliced mRNAs. During embryonic development 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 spinal cord. This shows that netrin-1 plays a major role in the adult brain and has the potential for therapeutic applications.^{[ citation needed ]}

Plasticity

Similar to growth cone guidance, synapse formation is cued by UNC-5 through a UNC-6 gradient that repels the dorsal axon migration.^[9] Dendritic filopodia extend from the dendritic 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 netrin is expressed by neurons in the corticospinal and rubrospinal projections, and by intrinsic neurons of the spinal cord both before and after the injury. When testing in vitro UNC-5 receptor bodies are taken from the spinal cord to neutralize netrin-1 in myelin. This increases the neurite outgrowth from UNC-5 expressing spinal motor neurons.^[10]

UNC-129

UNC-129 is a ligand in the transforming growth factor family in C. elegans 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.^[11] 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 axon guidance. Recent findings have shown that UNC-129 is also responsible for long range repulsive guidance of UNC-6.^[12] This mechanism enhances UNC-40 signaling while inhibiting UNC-5 alone. This causes an increase in sensitivity in growth cones 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 Caenorhabditis elegans.^[11]

Dendritic self avoidance

Recently it was found that dendrites do not overlap and actively avoid each other because cell specific membrane proteins trigger mutual repulsion.^[13] 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 dendritic 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 is not required for expression and dendritic self avoidance is independent of such a gradient. UNC-6 that binds to UNC-40 takes on different properties and functions as a short range guidance cue.^{[ citation needed ]}

Vertebrate laminins

Netrins share the same terminal structure with vertebrate laminins but appear minimally related. The basement membrane assembly across species, Vertebrate laminin-1 (α1β1γ1) and laminin-10 (α5β1γ1), like the two Caenorhabditis elegans laminins, are embryonically expressed and are essential for basement membrane assembly. During the basement assembly process laminins anchor to the cell surface through their G domains after polymerizing 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.^[14]

Applications

Tumorigenesis

Netrin-1 and its receptors DCC and UNC-5 show a new mechanism for induction or suppression regulation of apoptosis. 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 suppressor gene. However, the recent observations that DCC triggers cell death and is a receptor for netrin-1, a molecule recently implicated in colorectal tumorigenesis. The established role of DCC and netrin-1 during organization of the spinal cord 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 have renewed interest in the potential contribution of DCC inactivation to cancer. 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 apoptosis. The binding of netrin-1 to its receptors inhibits the tumor suppressor p53 dependent apoptosis.^[15] Such receptors share the property of inducing apoptosis in the absence of ligand, hence creating a cellular state of dependence on the ligand. Thus, netrin-1 may not only be a chemotropic factor for neurons but also a survival factor. This discovery shows that netrin-1 receptor pathways play an important role in tumorigenesis.^{[ citation needed ]}

Schwann cells

A study was performed to determine the effect of netrin-1 on schwann cell proliferation. Unc5b is the sole receptor 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. It was also found that the netrin-1-induced Schwann cell proliferation was blocked by the specific inhibition of Unc5b expression with RNAi. These data suggests that netrin-1 could be an endogenous trophic factor for Schwann cells in the injured peripheral nerves.^[14]

Related Research Articles

An axon, or nerve fiber, is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action potentials away from the nerve cell body. The function of the axon is to transmit information to different neurons, muscles, and glands. In certain sensory neurons, such as those for touch and warmth, the axons are called afferent nerve fibers and the electrical impulse travels along these from the periphery to the cell body and from the cell body to the spinal cord along another branch of the same axon. Axon dysfunction can be the cause of many inherited and acquired neurological disorders that affect both the peripheral and central neurons. Nerve fibers are classed into three types – group A nerve fibers, group B nerve fibers, and group C nerve fibers. Groups A and B are myelinated, and group C are unmyelinated. These groups include both sensory fibers and motor fibers. Another classification groups only the sensory fibers as Type I, Type II, Type III, and Type IV.

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 that impact the body, then works in tandem with the endocrine system to respond to such events. Nervous tissue first arose in wormlike organisms about 550 to 600 million years ago. In vertebrates it consists of two main parts, the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the brain and spinal cord. The PNS consists mainly of nerves, which are enclosed bundles of the long fibers or axons, that connect the CNS to every other part of the body. Nerves that transmit signals from the brain are called motor nerves or efferent nerves, while those nerves that transmit information from the body to the CNS are called sensory nerves or afferent. Spinal nerves are mixed nerves that serve both functions. The PNS is divided into three separate subsystems, the somatic, autonomic, and enteric nervous systems. Somatic nerves mediate voluntary movement. The autonomic nervous system is further subdivided into the sympathetic and the parasympathetic nervous systems. The sympathetic nervous system is activated in cases of emergencies to mobilize energy, while the parasympathetic nervous system is activated when organisms are in a relaxed state. The enteric nervous system functions to control the gastrointestinal system. Both autonomic and enteric nervous systems function involuntarily. Nerves that exit from the cranium are called cranial nerves while those exiting from the spinal cord are called spinal nerves.

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 field of neural development draws on both neuroscience and developmental biology to describe and provide insight into the cellular and molecular mechanisms by which complex nervous systems develop, from nematodes and fruit flies to mammals.

A motor nerve is a nerve that transmits motor signals from the central nervous system (CNS) to the muscles of the body. This is different from the motor neuron, which includes a cell body and branching of dendrites, while the nerve is made up of a bundle of axons. Motor nerves act as efferent nerves which carry information out from the CNS to muscles, as opposed to afferent nerves, which transfer signals from sensory receptors in the periphery to the CNS. Efferent nerves can also connect to glands or other organs/issues instead of muscles. In addition, there are nerves that serve as both sensory and motor nerves called mixed nerves.

Oligodendrocytes, also known as oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons within the central nervous system (CNS) of jawed vertebrates. Their function is similar to that of Schwann cells, which perform the same task in the peripheral nervous system (PNS). Oligodendrocytes accomplish this by forming the myelin sheath around axons. Unlike Schwann cells, a single oligodendrocyte can extend its processes to cover around 50 axons, with each axon being wrapped in approximately 1 μm of myelin sheath. Furthermore, an oligodendrocyte can provide myelin segments for multiple adjacent axons.

<span class="mw-page-title-main">Retinal ganglion cell</span> Type of cell within the eye

A retinal ganglion cell (RGC) is a type of neuron located near the inner surface of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and retina amacrine cells. Retina amacrine cells, particularly narrow field cells, are important for creating functional subunits within the ganglion cell layer and making it so that ganglion cells can observe a small dot moving a small distance. Retinal ganglion cells collectively transmit image-forming and non-image forming visual information from the retina in the form of action potential to several regions in the thalamus, hypothalamus, and mesencephalon, or midbrain.

Axon guidance 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 manage to find their way so accurately is an area of ongoing research.

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, netrin resembles the extracellular matrix protein laminin.

<span class="mw-page-title-main">Floor plate</span> Embryonic structure

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 from the midbrain to the tail regions. It has been shown that the floor plate is conserved among vertebrates, such as zebrafish and mice, with homologous structures in invertebrates such as the fruit fly Drosophila and the nematode C. elegans. Functionally, the structure serves as an organizer to ventralize tissues in the embryo as well as to guide neuronal positioning and differentiation along the dorsoventral axis of the neural tube.

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. Netrin receptor DCC is a single transmembrane receptor.

Slit homolog 2 protein is a protein that in humans is encoded by the SLIT2 gene.

Netrin-1 is a protein that in humans is encoded by the NTN1 gene.

Netrin receptor UNC5C is a protein that in humans is encoded by the UNC5C gene.

The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal cord is hollow and contains a structure called central canal, which contains cerebrospinal fluid. The spinal cord is also covered by meninges and enclosed by the neural arches. Together, the brain and spinal cord make up the central nervous system (CNS).

Slit is a family of secreted extracellular matrix proteins which play an important signalling role in the neural development of most bilaterians. While lower animal species, including insects and nematode worms, possess a single Slit gene, humans, mice and other vertebrates possess three Slit homologs: Slit1, Slit2 and Slit3. Human Slits have been shown to be involved in certain pathological conditions, such as cancer and inflammation.

Chondroitin sulfate proteoglycans (CSPGs) are proteoglycans consisting of a protein core and a chondroitin sulfate side chain. They are known to be structural components of a variety of human tissues, including cartilage, and also play key roles in neural development and glial scar formation. They are known to be involved in certain cell processes, such as cell adhesion, cell growth, receptor binding, cell migration, and interaction with other extracellular matrix constituents. They are also known to interact with laminin, fibronectin, tenascin, and collagen. CSPGs are generally secreted from cells.

Christine Elizabeth Holt FRS, FMedSci is a British developmental neuroscientist.

Slit-Robo is the name of a cell signaling protein complex with many diverse functions including axon guidance and angiogenesis.

The growth cone is a highly dynamic structure of the developing neuron, changing directionality in response to different secreted and contact-dependent guidance cues; it navigates through the developing nervous system in search of its target. The migration of the growth cone is mediated through the interaction of numerous trophic and tropic factors; netrins, slits, ephrins and semaphorins are four well-studied tropic cues (Fig.1). The growth cone is capable of modifying its sensitivity to these guidance molecules as it migrates to its target; this sensitivity regulation is an important theme seen throughout development.

UNC is a set of proteins first identified through a set of screening tests in Caenorhabditis elegans, looking for roundworms with movement problems. Worms with which were un-coordinated were analysed in order to identify the genetic defect. Such proteins include UNC-5, a receptor for UNC-6 which is one of the netrins. Netrins are a class of proteins involved in axon guidance. UNC-5 uses repulsion (genetics) to direct axons while the other netrin receptor UNC-40 attracts axons to the source of netrin production.

References

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