Neurotrophic Factors

Neurotrophic factors are secreted molecules that, for the most part, increase neuron survival. When neurons have nearly reached their target tissue during development neurotrophic factors are released by the target tissue.   Only enough for the survival of the number of connecting neurons required by the tissue is released, so any excess neurons die off through lack of neurotrophic factors.  Around 50% of the original number of neurons die at this stage.

As well as acting on the neuron as a whole, neurotrophic factors can also act locally on axons and dendrites to promote or inhibit the growth of individual branches.

Neurotrophic factors include:

Nerve Growth Factor (NGF)

 

  • Is essential for the survival of sensory neurons from the neural crest and sympathetic neurons.

 

  • Can also be needed for differentiation of neurons.

 

  • Is important after the phase of neuronal death for ensuring that the whole body surface is innervated and to make sure that innervation is restored after damage.

 

Brain Derived Neurotrophic Factor (BDNF)

 

  • Is called this because it was originally found in the brain but is now known to be used in the peripheral nervous system as well as other areas of the central nervous system.

 

  •  Stimulates the growth and differentiation of new neurons as well as maintaining the old ones. 

 

  • In the brain it is found in areas with roles in learning and memory; the hippocampus, cerebral cortex, cerebellum and basal forebrain.

 

  • In some cases can induce apoptosis rather than inhibit it.

 

Neurotrophin 3 (NT-3)

 

  • Can affect the largest number of neurons due to it having three different receptors.

 

  • Aids survival even before the neuron reaches its target.  Is heavily expressed along patterns of axon growth.

 

  • Acts on sensory and sympathetic  neurons in the peripheral nervous system and in the basal forebrain.

 

Neurotrophin 4 (NT-4)

 

  • Can also be called neurotrophin 5 or neurotrophin 4/5

 

NGF, BDNF and neurotrophins 3 and 4 make up the neurotrophin family. 

Neurotrophins are first formed as a precursor, or proneurotrophin, which is then cleaved by enzymes to form the mature protein.  The proneurotrophin can have the opposite effect to the neurotrophin, e.g. proNGF promotes apoptosis where as NGF itself promotes survival.

The receptors for this family are TrkA, TrkB, TrkC and p75.

Tropomyosin Related Kinase (Trk) Receptors

These are the high affinity receptors for the neurotrophin family.

 

 

NGF

BDNF

NT-3

NT-4

TrkA

     X

 

     X

     X

TrkB

 

     X

     X

     X

TrkC

 

 

     X

 

         X-Preferred binding couple

       X-Will bind, but with lower affinity

 

 

 

 All three are tyrosine kinase receptors. 

Trk receptors initiate a survival signal within the cell when bound by their ligand but it is not yet clear how this signal travels through the cell.  It is clear that the signal can travel over a distance from the tip of an axon to the cell body.

 

P75 Receptor

This is activated by all the neurotrophins but with low affinity.  It is a member of the tumour necrosis factor (TNFR) family of receptors.

P75R does not appear to have a set role in neuron survival as it can both increase and decrease neuronal survival.

It is thought to associate with the Trk receptors to enhance ligand binding and phosphorylation as well as binding the ligand itself.

 

There are many other neurotrophic factors besides the neurotrophins, here are a few examples;

 

Ciliary neurotrophic factor (CNTF)

 

  • Is a cytokine that is released by glial cells

 

  • Promotes the survival of sensory and motor neurons.

 

  • Is used to treat neurodegenerative disorders such as motor neuron disease and is being considered for the treatment of Huntington's disease.

 

Hepatocyte Growth Factor/ Scatter Factor (HGF/ SF)

 

  • A cytokine

 

  • Affects motor neurons

 

Glial Derived Neurotrophic factor (GDNF)

 

  • Is a survival factor for motor and dopaminergic neurons.

 

  • Belongs to the TGF-beta family.

 

Insulin-like growth factor-1 (IGF-1)

 

  • The name comes from its structural similarity to insulin. 

 

  • Is released by the liver in response to growth hormone.

 

  • Plays a role in maintaining normal physiology, including the inhibition of apoptosis.

 

Hormones

While hormones are not necessarily classed as neurotrophic factors endocrine signalling can support the survival of a cell.  Steroid hormones cross the plasma membrane and enter the nucleus where they affect gene transcription.

RatExperiments have shown that withdrawing the supply of sex hormone from male rats through castration leads to increased neuronal death in the superior cervical ganglion.  Treatment before birth with sex hormone improves survival in this area.  The hormone could be both oestrogen and testosterone and had the same effect in females.  Similar patterns are seen in motor neurons.

Image from Wikimedia Commons https://commons.wikimedia.org/wiki/File:Albino_Rat.jpg, in public domain

Contact

Alison Ruff