Netrin
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Netrins are a class of
.Netrins are
A proposed
Discovery
Netrin was first described in the nematode
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
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-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
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
Attraction
Studies of
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
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
Glial and mesodermal guidance
Many studies have shown that
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
During the morphogenesis of the embryonic lung,
In
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
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,
See also
- Neural development
- Axon guidance
- Pioneer neuron
- Pioneer axon
- Neural development in humans
- Human brain development timeline
- Roundabout gene
- Slit gene
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- Online Mendelian Inheritance in Man (OMIM): NETRIN 1, MOUSE, HOMOLOG OF; NTN1 - 601614
- Wade, Nicholas, ed. (1998). The Science Times Book of the Brain. The Lyons Press. ISBN 9781558216532.