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Neurotrophins

Posted by Chris on May 23rd, 2013  ⟩  0 comments

It is a still a commonly held belief that nerve damage can never be healed or repaired sufficiently to regain use. But in recent years that dogmatic view has been successfully challenged and refuted by our ever-growing understanding of growth factors, specifically the Neurotrophins, and their relationships with stem cells. Neurotrophins are neuronal factors which are important regulators of neural development, function and survival. Neurotrophins are key components of Neural Stem Cells (NSCs), which are primordial and uncommitted cells that have been believed to give rise to the vast array of more specialized cells of the CNS which are defined by their ability to (1) to differentiate into cells of all neural lineages in multiple regional and developmental contexts; (2) to self-renew; (3) to migrate and populate developing and/or degenerating CNS regions; and (4) to have biofunctional multipotency to mediate systemic homeostasis through capacities such as production of trophic factors, formation of gap junctions, etc. (Teng, 2011).

Since the original discovery of Nerve Growth Factor (NGF) in the 1960’s by Cohen and Levi-Montalcini, the class of neurotrophic factors has grown to just 4 official neurotrophins: NGF, Brain derived neurotrophic factor (BDNF), Neurotrophin 3 (NTF3, and Neurotrophin 4 (NTF4). But the class has also grown to typically include the GDNF (Glial cell-derived neurotrophic factors) as well as the CNTF (Ciliary neurotrophic factor) families of ligands.

NTF ReceptorsNeurotrophins are defined by their expression as well as their neuronal targets, which typically contain an appropriate trk receptor, which are transmembrane tyrosine kinases that specifically bind to neurotrophins. There are 3 trk receptors: trkA, which primarily binds and is activated by NGF; trkB, which binds and is activated primarily by BDNF and TNF4 and to a lesser extent NTF3; and trkC, which binds and is activated by NTF3. There is an additional family of receptors called the P75 neurotrophin receptor, or Low-affinity Nerve Growth Factor Receptor (LNGFR). All 4 of the neurotrophins are known to bind to the LNGFR, though the precise function of the P75 receptor is still not well understood. (For another wonderful general review of neurotrophins (and where I borrowed this great illustration), you should visit Betarhyme.)

Neurotrophins are primarily present in the development of the nervous system and responsible for the initial growth of neurons and the central nervous system. After development, they are also capable of promoting neural cell repair and even neural re-growth; exciting prospects for research projects concerning ALS or even Alzheimer’s. Shen et al. (2010) recently found that NTF4 suppresses the Il6 receptor and the Notch signaling pathway, suggesting an interesting, potential signaling cascade in neurogenesis. Below is their proposed signaling pathway for the differentiation of NSCs into neuronal progenitors.

NTF4 Signaling-Shen 2010

GDNF is another neurotrophic factor that is usually considered to be under the greater family of neurotrophins. GNDF is most notable for its promotion and support of motorneurons and dopamine neurons. The loss of motorneuron populations are complication of neural degradation diseases such as Parkinson’s disease as well as ALS. GNDF primarily binds through GDNF family receptor-α1 (GFRα1), which facilitates the binding of RET molecules, a receptor tyrosine kinase (Ghitza, 2011). RET activation is involved in neuronal survival, differentiation and proliferation, neurite outgrowth, and synaptic plasticity (Sariola and Saarma, 2003).

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Teng, Y. D., Yu, D., Ropper, A. E., Li, J., Kabatas, S., Wakeman, D. R., ... & Sidman, R. L. (2011). Functional multipotency of stem cells: a conceptual review of neurotrophic factor-based evidence and its role in translational research. Current neuropharmacology, 9(4), 574.

Shen, Y., Inoue, N., & Heese, K. (2010). Neurotrophin-4 (ntf4) mediates neurogenesis in mouse embryonic neural stem cells through the inhibition of the signal transducer and activator of transcription-3 (stat3) and the modulation of the activity of protein kinase B. Cellular and molecular neurobiology, 30(6), 909-916.

Ghitza, U. E., Zhai, H., Wu, P., Airavaara, M., Shaham, Y., & Lu, L. (2010). Role of BDNF and GDNF in drug reward and relapse: a review. Neuroscience & Biobehavioral Reviews, 35(2), 157-171.

Sariola, H., & Saarma, M. (2003). Novel functions and signalling pathways for GDNF. Journal of Cell Science, 116(19), 3855-3862.

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