Netrin-1 is a protein that in humans is encoded by the NTN1 gene. [5] [6]
Netrin is included in a family of laminin-related secreted proteins. The function of this gene has not yet been defined; however, netrin is thought to be involved in axon guidance and cell migration during development. Mutations and loss of expression of netrin suggest that variation in netrin may be involved in cancer development. [6]
NTN1 has been shown to interact with Deleted in Colorectal Cancer, [5] [7] and components of the extracellular matrix and the tumor microenvironment. [8]
During the development of the central nervous system, when the dorsal and ventral signaling is being established, the floor plate is an important site for crossing for groups of neural processes at the dorsal midline. Once crossed through the floor plate, these groups are now referred to as commissural axons. These neuronal cell bodies are signaled by Netrin 1 to be attracted to the floor plate from the dorsal half of the neural tube. NTN1 is a gene that encodes for the protein, Netrin-1. In a study done in knockout mice with a depletion of floor plate Netrin-1, it was shown that corticospinal axon tract midline crossing was disrupted. [9] This study was done to show characteristics of patients with human congenital mirror movement disorder.
Afterwards, proper positioning of axons and midline crossing are pioneered by the Slit-Robo system where Slit proteins act as axonal repellents and Robo proteins (Robo-1, Robo-2, Robo-3) act in conjunction with Slit ligands to be their receptors. [10] Slit with Robo-1 and Robo-2 repel axonal extension at the midline thereby commissural axons expressing Robo-3 cross the midline by interfering with Slit/Robo-1, Robo-2 repulsive activity. After crossing the floor plate, Robo-3 is downregulated and Slit/Robo-1, Robo-2 continue to express their repulsiveness at the midline. Furthermore, mutations in Robo-3 cause horizontal gaze palsy with progressive scoliosis.
In neuroanatomy, the optic chiasm, or optic chiasma, is the part of the brain where the optic nerves cross. It is located at the bottom of the brain immediately inferior to the hypothalamus. The optic chiasm is found in all vertebrates, although in cyclostomes, it is located within the brain.
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.
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.
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.
Slit homolog 2 protein is a protein that in humans is encoded by the SLIT2 gene.
Roundabout homolog 1 is a protein that in humans is encoded by the ROBO1 gene.
Roundabout homolog 2 is a protein that in humans is encoded by the ROBO2 gene.
Netrin receptor UNC5C is a protein that in humans is encoded by the UNC5C gene.
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.
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.
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.
Alain Chédotal is a French researcher specialising in the development of neural circuits. He has been a member of the French Academy of sciences since 2017.
Patrick Mehlen, is a French biologist and research director at the Centre national de recherche scientifique (CNRS) at the Centre Léon-Bérard, a cancer research centre in Lyon.
Esther Stoeckli is a Swiss neuroscientist at the University of Zurich and the director of the Institute of Molecular Life Sciences. Her research focuses on the molecular mechanisms that underlie the establishment of neuronal circuits.
Varadarajan, Supraja G., et al. "Netrin1 produced by neural progenitors, not floor plate cells, is required for axon guidance in the spinal cord." Neuron 94.4 (2017): 790-799. https://doi.org/10.1016/j.neuron.2017.03.007
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