Neurotrophic Factors

Definition
Neurotrophic factors are small proteins that exert survival-promoting and trophic (derived from the Greek meaning "to nourish") actions on neuronal (or nerve) cells1.

Related Peptides
The neurotrophic factors, a subclass of growth factors, act on neurons as well as other non-neuronal cells. This subclass of factors contains at least three distinct families: the neurotrophins (e.g., NGF: brain-derived neurotrophic factor, BDNF: and neurotrophins NT-3 and NT-4/5); the neuropoietic cytokines (e.g., ciliary neurotrophic factor, CNTF); and the fibroblast growth factors (e.g., acidic and basic FGF). The members of these families of neurotrophic factors demonstrate significant (50% or more) homology and have affinities for particular classes of receptors.

Proteins with well-documented neurotrophic activity:
Acidic fibroblast growth factor (aFGF)
Basic fibroblast growth factor (bFGF)
Brain-derived neurotrophic factor (BDNF)
Ciliary neurotrophic factor (CNTF)
Interleukin 1, 3 and 6 (IL-1, 3, 6)
Neurotrophin-3 (NT-3)
Neurotrophin-4/5 (NT-4/5)
Nerve growth factor (NGF)
Glial-derived neurotrophic factor (GDNF)
Proteins with putative neurotrophic activity:
Cholinergic neuronal differentiation factor (CDF)
Epidermal growth factor (EGF)
Heparin binding neurotrophic factor (HBNF)
Insulin
Insulin like growth factors (IGFs)
Protease nexin I and II
Transforming growth factor alpha (TGFalpha) 1.

Discovery
The discovery of nerve growth factor (NGF) by Rita Levi-Montalcini in the 1950s represents an important milestone in the processes that led to modern cell biology. NGF was the first growth factor identified, for its action on the morphological differentiation of neural-crest-derived nerve cells. Later, its effect on neuronal cells of the peripheral and central nervous system, and on several non-neuronal cells was also determined. Thus, Levi-Montalcini's work on NGF represents, as acknowledged by the Nobel Prize Assembly in its press release of 13 October 1986, ‘a fascinating example of how a skilled observer can create a concept out of apparent chaos’ 2, 3.

Structural Characteristics
These molecules are generally small, soluble proteins with molecular weights between 13-24kDa and are often active as homodimers1.

Mode of Action
Neurotrophic factors bind to a low affinity receptor (p75) and to a family of closely related high affinity glycoprotein tyrosine receptor kinases (Trk molecules). The receptor topology for the neuropoietic cytokines is very different. The transduction pathway for CNTF, for example, involves a tyrosine kinase, but the receptor itself is not a tyrosine kinase. The CNTF receptor consists of a complex of three subunits, only one of which directly binds CNTF, and the tyrosine kinase JAK/TYK, which associates with the CNTF receptor complex on the cytosolic side of the plasma membrane. The binding of the FGFs on the other hand is different from the other neurotrophic factors in that it involves a low affinity binding site related to heparin sulfate and a high affinity receptor that contains a tyrosine kinase. Unlike most known receptor molecules, all these tyrosine kinase receptors possess only one transmembrane domain. The first step in their activation by growth factors always involves receptor oligomerization, which seems to be the initial signal transduction event that leads to tyrosine kinase activation. Not only are the receptor mechanisms comparable for the various neurotrophic factors, but also the intracellular signaling pathways are very similar, even for such diverse molecules as NGF, CNTF and FGF. Thus, a large group of diverse factors act on distinct receptors, leading to similar intracellular molecular changes which can profoundly impact neuron development and survival.

Functions
During development, these factors play a critical role in mediating the ability of a target (e.g., skeletal muscle) of a neuron (e.g., spinal cord motor neuron) to prevent the death of the nerve cell. In addition to these effects on neuronal survival, neurotrophic factors play a critical role in the "quality of life" of neurons. Neurotrophic factors regulate growth of neurons, associated metabolic functions such as protein synthesis, and the ability of the neuron to make the neurotransmitters that carry chemical signals which allow the neuron to communicate with other neurons or with other targets (muscles, glands, etc.). Because of these actions, neurotrophic factors play a significant role in the maintenance of neuronal function throughout an individual's entire lifetime1.

References
1.Lipton P, Kalil R. (1995). Neurotrophic Factors - An Overview. Promega Notes Magazine., 50:.18-21.
2.Aloe L. (2004). Rita Levi-Montalcini: the discovery of nerve growth factor and modern neurobiology. Trends in Cell Biology. 14(7):395-399.
3.Cohen, S., Levi-Montalcini, R. Hamburger.(1954). A nerve growth stimulating factor isolated from sarcoma as 37 and 180. PNAS., 1 40(10): 1014–1018.

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