Netrin

Last updated
Netrin 1 knockout disrupts thalamocortical projections topography in the mouse brain. From Powell et al., 2008. Netrin 1 knockout model cropped.png
Netrin 1 knockout disrupts thalamocortical projections topography in the mouse brain. From Powell et al., 2008.

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, [2] fruit flies, frogs, mice, and humans. Structurally, netrin resembles the extracellular matrix protein laminin.

Contents

Netrins are chemotropic; a growing axon will either move towards or away from a higher concentration of netrin. Though the detailed mechanism of axon guidance is not fully understood, it is known that netrin attraction is mediated through UNC-40/DCC cell surface receptors and repulsion is mediated through UNC-5 receptors. Netrins also act as growth factors, encouraging cell growth activities in target cells. Mice deficient in netrin fail to form the hippocampal comissure or the corpus callosum.

A proposed model for netrin activity in the spinal column of developing human embryos is that netrins are released by the floor plate and then are picked up by receptor proteins embedded in the growth cones 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. Research supports that new axons tend to follow previously traced pathways rather than being guided by netrins or related chemotropic factors. [3]

Discovery

Netrin was first described in the nematode Caenorhabditis elegans in 1990, and named UNC-6, according to standard C. elegans naming protocol. [4] 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. [2] 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 tails. All netrins discovered in invertebrates thus far are secreted. [5]

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, they can act as long or short range signals during neurogenesis. In order to carry out their functions, netrins interact with specific receptors: DCC or UNC-5, 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. [6]

Key netrins

Netrin-1 is found in the floor plate and neuroepithelial cells 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. [7] Its main role is in axonal guidance, neuronal migration and morphogenesis 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. [8]

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. [7] 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 Glycophosphatidylinositol (GPI). They are expressed predominantly in the central nervous system in places such as the thalamus and mitral cells of the olfactory bulb. [7] 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 UNC-5 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 of epithelial cells. In the absence of netrin-1, these receptors are known to induce apoptosis. [7]

Axonal guidance

Growth cones that are located at the end of developing axons during embryogenesis are responsible for the elongation of the axon during migration. 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 and the zebrafish Danio rerio 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). [6]

Attraction

Studies of central nervous system (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 floor plate 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 (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. corpus callosum) 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 [9] 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. [5] [10]

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 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, 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 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 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 protein WASP trigger Rac1 and Cdc42 and subsequently axonal growth. [11] [12] [13]

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 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 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. [5] [14]

It is currently hypothesized that long range chemorepulsion involves initiation of the Arachidonic acid 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 (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 to the netrin-1/UNC-5 complex may also trigger chemorepulsion through RhoA. [15]

Glial and mesodermal guidance

Many studies have shown that netrin-1, UNC-40, UNC-6, and UNC-5 are involved in the migration of glia during embryogenesis. [16] [17] 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. [17] UNC-6 signaling in C. elegans, coupled with the UNC-40 receptor on neurons, promotes synaptogenesis and assembles the glial endfeet around the synapse. [18]

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 morphogenesis by controlling developing cell migration and cell adhesion in different organs. [19]

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. [19] [20]

During the morphogenesis of the embryonic lung, epithelial cells express netrin 1 and netrin 4. These netrins surround endoderm buds in the basement membrane, 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. [19]

In pancreatic development, netrin 1 is expressed in epithelial ductal cells and localizes to the basal membrane. Netrin 1 associates with several elements in the extracellular matrix, including collagen IV, fibronectin, 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. [19] [21]

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. 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. [19] [22]

In adults, netrin has been implicated in the regulation of stem cell 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. [19] [23]

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. This pathway is unique and independent of the mitochondrial and death receptor 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 is responsible for the expression of netrin-1, implying that netrin may be the pathway through which p53 regulates the cell cycle. Because netrin is so influential in the regulation of cell death, the gene which codes for netrin (NTN1) is considered to be an oncogene. [24]

Because netrin-1 has been found to be upregulated in tumors, recent research has attempted to identify netrin-1 as a biomarker 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. [25] 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. [26]

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 chemorepulsion. 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. [27]

Another important line of current research targets netrin as a treatment for various diseases, including cancer, myocardial infarction, and Alzheimer's disease. In avian and mouse model organisms suffering from neuroblastoma, interfering with the netrin-1 autocrine loop in malignant tumors leads to cell death. [28] 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. [29] 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 in Alzheimer's disease. [30]

See also

Related Research Articles

<span class="mw-page-title-main">Axon</span> Long projection on a neuron that conducts signals to other neurons

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.

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.

<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.

<span class="mw-page-title-main">Floor plate (biology)</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.

<span class="mw-page-title-main">Ephrin receptor</span> Protein family

Eph receptors are a group of receptors that are activated in response to binding with Eph receptor-interacting proteins (Ephrins). Ephs form the largest known subfamily of receptor tyrosine kinases (RTKs). Both Eph receptors and their corresponding ephrin ligands are membrane-bound proteins that require direct cell-cell interactions for Eph receptor activation. Eph/ephrin signaling has been implicated in the regulation of a host of processes critical to embryonic development including axon guidance, formation of tissue boundaries, cell migration, and segmentation. Additionally, Eph/ephrin signaling has been identified to play a critical role in the maintenance of several processes during adulthood including long-term potentiation, angiogenesis, and stem cell differentiation and cancer.

<span class="mw-page-title-main">Netrin receptor DCC</span> Protein-coding gene in the species Homo sapiens

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.

Pioneer axon is the classification given to axons that are the first to grow in a particular region. They originate from pioneer neurons, and have the main function of laying down the initial growing path that subsequent growing axons, dubbed follower axons, from other neurons will eventually follow.

<span class="mw-page-title-main">Ephrin</span> Family of proteins

Ephrins are a family of proteins that serve as the ligands of the Eph receptor. Eph receptors in turn compose the largest known subfamily of receptor protein-tyrosine kinases (RTKs).

<span class="mw-page-title-main">ROBO1</span> Protein-coding gene in the species Homo sapiens

Roundabout homolog 1 is a protein that in humans is encoded by the ROBO1 gene.

<span class="mw-page-title-main">Netrin 1</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">Roundabout family</span>

The Roundabout (Robo) family of proteins are single-pass transmembrane receptors that are highly conserved across many branches of the animal kingdom, from C. elegans to humans. They were first discovered in Drosophila, through a mutant screen for genes involved in axon guidance. The Drosophila roundabout mutant was named after its phenotype, which resembled the circular traffic junctions. The Robo receptors are most well known for their role in the development of the nervous system, where they have been shown to respond to secreted Slit ligands. One well-studied example is the requirement for Slit-Robo signaling in regulation of axonal midline crossing. Slit-Robo signaling is also critical for many neurodevelopmental processes including formation of the olfactory tract, the optic nerve, and motor axon fasciculation. In addition, Slit-Robo signaling contributes to cell migration and the development of other tissues such as the lung, kidney, liver, muscle and breast. Mutations in Robo genes have been linked to multiple neurodevelopmental disorders in humans.

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.

<span class="mw-page-title-main">Chondroitin sulfate proteoglycan</span>

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 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.

<span class="mw-page-title-main">Tropic cues involved in growth cone guidance</span>

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.

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.

A follower neuron is a nerve cell that arises in the developmental stage of the brain and which growth and orientation is intrinsically related to pioneer neurons. These neurons can also be called later development neurons or follower cells. In the early stages of brain development, pioneer neurons define axonal trajectories that are later used as scaffolds by follower neurons, which project their growth cones and fasciculate with pioneer axons, forming a fiber tract and demonstrating a preference for axon-guided growth. It is thought that these neurons can read very accurate cues of direction and fasciculate or defasciculate in order to reach their target, even in a highly dense axon bundle.

References

  1. ↑ Powell, Ashton W.; Sassa, Takayuki; Wu, Yongqin; Tessier-Lavigne, Marc; Polleux, Franck (2008). Ghosh, Anirvan (ed.). "Topography of Thalamic Projections Requires Attractive and Repulsive Functions of Netrin-1 in the Ventral Telencephalon". PLOS Biology. 6 (5): e116. doi: 10.1371/journal.pbio.0060116 . PMC   2584572 . PMID   18479186.
  2. 1 2 Serafini, Tito; Kennedy, Timothy E.; Galko, Michael J.; Mirzayan, Christine; Jessell, Thomas M.; Tessier-Lavigne, Marc (1994). "The netrins define a family of axon outgrowth-promoting proteins homologous to C. Elegans UNC-6". Cell. 78 (3): 409–24. doi:10.1016/0092-8674(94)90420-0. PMID   8062384. S2CID   22666205.
  3. ↑ Kennedy, Timothy E.; Serafini, Tito; De La Torre, Josér.; Tessier-Lavigne, Marc (1994). "Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord". Cell. 78 (3): 425–35. doi:10.1016/0092-8674(94)90421-9. PMID   8062385. S2CID   20986509.
  4. ↑ Hedgecock, Edward M.; Culotti, Joseph G.; Hall, David H. (1990). "The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. Elegans". Neuron. 4 (1): 61–85. doi:10.1016/0896-6273(90)90444-K. PMID   2310575. S2CID   23974242.
  5. 1 2 3 Rajasekharan, Sathyanath; Kennedy, Timothy E (2009). "The netrin protein family". Genome Biology. 10 (9): 239. doi: 10.1186/gb-2009-10-9-239 . PMC   2768972 . PMID   19785719.
  6. 1 2 Dickson, B. J. (2002). "Molecular Mechanisms of Axon Guidance". Science. 298 (5600): 1959–64. Bibcode:2002Sci...298.1959D. doi:10.1126/science.1072165. PMID   12471249. S2CID   28328792.
  7. 1 2 3 4 Barallobre, María J.; Pascual, Marta; Del Río, José A.; Soriano, Eduardo (2005). "The Netrin family of guidance factors: Emphasis on Netrin-1 signalling". Brain Research Reviews. 49 (1): 22–47. doi:10.1016/j.brainresrev.2004.11.003. PMID   15960985. S2CID   46662140.
  8. ↑ Jiang, Shan; Richaud, Mathieu; Vieugué, Pauline; Rama, Nicolas; Delcros, Jean-Guy; Siouda, Maha; Sanada, Mitsuaki; Redavid, Anna-Rita; Ducarouge, Benjamin; Hervieu, Maëva; Breusa, Silvia; Manceau, Ambroise; Gattolliat, Charles-Henry; Gadot, Nicolas; Combaret, Valérie; Neves, David; Ortiz-Cuaran, Sandra; Saintigny, Pierre; Meurette, Olivier; Walter, Thomas; Janoueix-Lerosey, Isabelle; Hofman, Paul; Mulligan, Peter; Goldshneider, David; Mehlen, Patrick; Gibert, Benjamin (2021). "Targeting netrin-3 in small cell lung cancer and neuroblastoma". EMBO Molecular Medicine. 13 (4): e12878. doi:10.15252/emmm.202012878. PMC   8033513 . PMID   33719214.
  9. ↑ Norris, A. D.; Lundquist, E. A. (2011). "UNC-6/netrin and its receptors UNC-5 and UNC-40/DCC modulate growth cone protrusion in vivo in C. Elegans". Development. 138 (20): 4433–42. doi:10.1242/dev.068841. PMC   3177313 . PMID   21880785.
  10. ↑ Bashaw, G. J.; Klein, R. (2010). "Signaling from Axon Guidance Receptors". Cold Spring Harbor Perspectives in Biology. 2 (5): a001941. doi:10.1101/cshperspect.a001941. PMC   2857166 . PMID   20452961.
  11. ↑ Bradford, Danakai; Cole, Stacey J.; Cooper, Helen M. (2009). "Netrin-1: Diversity in development". The International Journal of Biochemistry & Cell Biology. 41 (3): 487–93. doi:10.1016/j.biocel.2008.03.014. PMID   18455953.
  12. ↑ Dent, E. W.; Barnes, AM; Tang, F; Kalil, K (2004). "Netrin-1 and Semaphorin 3A Promote or Inhibit Cortical Axon Branching, Respectively, by Reorganization of the Cytoskeleton". Journal of Neuroscience. 24 (12): 3002–12. doi: 10.1523/JNEUROSCI.4963-03.2004 . PMC   6729836 . PMID   15044539.
  13. ↑ Causeret, F.; Hidalgo-Sanchez, M; Fort, P; Backer, S; Popoff, MR; Gauthier-Rouvière, C; Bloch-Gallego, E (2004). "Distinct roles of Rac1/Cdc42 and Rho/Rock for axon outgrowth and nucleokinesis of precerebellar neurons toward netrin 1". Development. 131 (12): 2841–52. doi: 10.1242/dev.01162 . PMID   15151987.
  14. ↑ Jarjour, Andrew A.; Manitt, Colleen; Moore, Simon W.; Thompson, Katherine M.; Yuh, Sung-Joo; Kennedy, Timothy E. (2003). "Netrin-1 Is a Chemorepellent for Oligodendrocyte Precursor Cells in the Embryonic Spinal Cord". The Journal of Neuroscience. 23 (9): 3735–44. doi:10.1523/JNEUROSCI.23-09-03735.2003. PMC   6742169 . PMID   12736344.
  15. ↑ Nishiyama, Makoto; Hoshino, Akemi; Tsai, Lily; Henley, John R.; Goshima, Yoshio; Tessier-Lavigne, Marc; Poo, Mu-Ming; Hong, Kyonsoo (2003). "Cyclic AMP/GMP-dependent modulation of Ca2+ channels sets the polarity of nerve growth-cone turning". Nature. 423 (6943): 990–5. Bibcode:2003Natur.423..990N. doi:10.1038/nature01751. PMID   12827203. S2CID   4409042.
  16. ↑ Chen, Hongwei; Wei, Qiang; Zhang, Jing; Xu, Chuangkun; Tan, Tao; Ji, Weizhi (2010). "Netrin-1 signaling mediates NO-induced glial precursor migration and accumulation". Cell Research. 20 (2): 238–41. doi: 10.1038/cr.2010.7 . PMID   20084084.
  17. 1 2 Von Hilchen, C. M.; Hein, I.; Technau, G. M.; Altenhein, B. (2010). "Netrins guide migration of distinct glial cells in the Drosophila embryo". Development. 137 (8): 1251–62. doi: 10.1242/dev.042853 . PMID   20223758.
  18. ↑ Colon-Ramos, D. A.; Margeta, M. A.; Shen, K. (2007). "Glia Promote Local Synaptogenesis Through UNC-6 (Netrin) Signaling in C. Elegans". Science. 318 (5847): 103–6. Bibcode:2007Sci...318..103C. doi:10.1126/science.1143762. PMC   2741089 . PMID   17916735.
  19. 1 2 3 4 5 6 Sun, K. L. W.; Correia, J. P.; Kennedy, T. E. (2011). "Netrins: Versatile extracellular cues with diverse functions". Development. 138 (11): 2153–69. doi: 10.1242/dev.044529 . PMID   21558366.
  20. ↑ Srinivasan, Karpagam; Strickland, Phyllis; Valdes, Ana; Shin, Grace C; Hinck, Lindsay (2003). "Netrin-1/Neogenin Interaction Stabilizes Multipotent Progenitor Cap Cells during Mammary Gland Morphogenesis". Developmental Cell. 4 (3): 371–82. doi: 10.1016/S1534-5807(03)00054-6 . PMID   12636918.
  21. ↑ Yebra, Mayra; Montgomery, Anthony M.P.; Diaferia, Giuseppe R.; Kaido, Thomas; Silletti, Steve; Perez, Brandon; Just, Margaret L.; Hildbrand, Simone; Hurford, Rosemary; Florkiewicz, Elin; Tessier-Lavigne, M; Cirulli, V (2003). "Recognition of the Neural Chemoattractant Netrin-1 by Integrins α6β4 and α3β1 Regulates Epithelial Cell Adhesion and Migration". Developmental Cell. 5 (5): 695–707. doi: 10.1016/S1534-5807(03)00330-7 . PMID   14602071.
  22. ↑ Xie, H.; Zou, L.; Zhu, J.; Yang, Y. (2011). "Effects of netrin-1 and netrin-1 knockdown on human umbilical vein endothelial cells and angiogenesis of rat placenta". Placenta. 32 (8): 546–53. doi:10.1016/j.placenta.2011.04.003. PMID   21570114.
  23. ↑ Petit, Audrey; Sellers, Drew L.; Liebl, Daniel J.; Tessier-Lavigne, Marc; Kennedy, Timothy E.; Horner, Philip J. (2007). "Adult spinal cord progenitor cells are repelled by netrin-1 in the embryonic and injured adult spinal cord". Proceedings of the National Academy of Sciences. 104 (45): 17837–42. Bibcode:2007PNAS..10417837P. doi: 10.1073/pnas.0703240104 . JSTOR   25450329. PMC   2077035 . PMID   17978191.
  24. ↑ Arakawa, Hirofumi (2004). "Netrin-1 and its receptors in tumorigenesis". Nature Reviews Cancer. 4 (12): 978–87. doi:10.1038/nrc1504. PMID   15573119. S2CID   867903.
  25. ↑ Ramesh, Ganesan; Berg, Arthur; Jayakumar, Calpurnia (2011). "Plasma netrin-1 is a diagnostic biomarker of human cancers". Biomarkers. 16 (2): 172–80. doi:10.3109/1354750X.2010.541564. PMC   3143477 . PMID   21303223.
  26. ↑ Jiang, Shan; Richaud, Mathieu; Vieugué, Pauline; Rama, Nicolas; Delcros, Jean-Guy; Siouda, Maha; Sanada, Mitsuaki; Redavid, Anna-Rita; Ducarouge, Benjamin; Hervieu, Maëva; Breusa, Silvia; Manceau, Ambroise; Gattolliat, Charles-Henry; Gadot, Nicolas; Combaret, Valérie; Neves, David; Ortiz-Cuaran, Sandra; Saintigny, Pierre; Meurette, Olivier; Walter, Thomas; Janoueix-Lerosey, Isabelle; Hofman, Paul; Mulligan, Peter; Goldshneider, David; Mehlen, Patrick; Gibert, Benjamin (15 March 2021). "Targeting netrin-3 in small cell lung cancer and neuroblastoma". EMBO Molecular Medicine. 13 (4): e12878. doi: 10.15252/emmm.202012878 . PMC   8033513 . PMID   33719214.
  27. ↑ Guthrie, Sarah (1997). "Axon guidance: Netrin receptors are revealed". Current Biology. 7 (1): R6–9. doi: 10.1016/S0960-9822(06)00007-8 . PMID   9072174. S2CID   1150696.
  28. ↑ Delloye-Bourgeois, Céline; Fitamant, Julien; Paradisi, Andrea; Cappellen, David; Douc-Rasy, Setha; Raquin, Marie-Anne; Stupack, Dwayne; Nakagawara, Akira; Rousseau, Raphaël; Combaret, Valérie; Puisieux, Alain; Valteau-Couanet, Dominique; Bénard, Jean; Bernet, Agnès; Mehlen, Patrick (2009). "Netrin-1 acts as a survival factor for aggressive neuroblastoma". Journal of Experimental Medicine. 206 (4): 833–47. doi:10.1084/jem.20082299. PMC   2715117 . PMID   19349462.
  29. ↑ Fitamant, Julien; Guenebeaud, Céline; Coissieux, Marie-May; Guix, Catherine; Treilleux, Isabelle; Scoazec, Jean-Yves; Bachelot, Thomas; Bernet, Agnès; Mehlen, Patrick (2008). "Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer". Proceedings of the National Academy of Sciences. 105 (12): 4850–5. Bibcode:2008PNAS..105.4850F. doi: 10.1073/pnas.0709810105 . JSTOR   25461511. PMC   2290782 . PMID   18353983.
  30. ↑ Zhang, Jun; Cai, Hua (2010). "Netrin-1 prevents ischemia/reperfusion-induced myocardial infarction via a DCC/ERK1/2/eNOSs1177/NO/DCC feed-forward mechanism". Journal of Molecular and Cellular Cardiology. 48 (6): 1060–70. doi:10.1016/j.yjmcc.2009.11.020. PMC   2866819 . PMID   20004665.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.