Cells of multi-cellular organisms not only require oxygen and nutrients to survive, they also need survival signals called trophic factors. In the absence of such signals, signaling pathways that prevent the cell to undergo a “suicide” program are not activated and, thus, result in cell death.
Analysis of the development of the nervous system demonstrated the essentiality of trophic factors in cellular development. Indeed, it was shown that more cells grew than actually survived when neurons developed to connect to other neurons (or muscles), even over long distances. It was further demonstrated that only those cells that succeeded in making connections survived while the others died.
An example of such trophic factors was discovered through the study of innervation of developing limbs in chick embryos and was simply known as nerve growth factor (NGF). It was then identified to belong to the neurotrophins, which binds to and activate a family of receptor tyrosine kinases called Trk. NGF binds with high affinity to TrkA and, through this binding, provides the necessary surviving signal to avoid “suicide” for different classes of neurons that successfully made connections. Indeed, only Trk receptors produced on the growth cones of the extending axons of neurons trying to make connections bind neurotrophins produced by target tissues.
This process is key during developmental processes as it ensures that the right neurons survive and in the required amount for proper target innervation. Furthermore, neurotrophins allow for cell fate decision, axon growth, dendrite pruning, the patterning of innervation and the expression of proteins crucial for normal neuronal function, such as neurotransmitters and ion channels. Neurotrophins were also found to regulate many aspects of neural function, e.g. in the mature nervous system, they were demonstrated to control synaptic function and synaptic plasticity, while continuing to modulate neuronal survival.
- Lodish et al., Molecular Cell Biology, Sixth Edition, 2008, pp. 936-938
- Neurotrophins: roles in neuronal development and function, Huang EJ, Reichardt LF., Annu Rev Neurosci. 2001;24:677-736. Review.