What is the Importance of Multivesicular Bodies in Retrograde Axonal Transport In Vivo?

Abstract

Neurons with long axons have a unique problem in generating signaling cascades that are able to reach the nucleus after receptor activation by neurotrophins at the nerve terminal. The straightforward concept of receptor binding and local generation of 2nd second messenger cascades is too simplistic. In this review we will outline a mechanism that would enable the complex signals generated at the nerve terminal to be conveyed intact to the cell body. There are three different sites in the neuron where 2nd messenger proteins can interact with the signaling complex and be activated. Signaling cascades are initiated both at the nerve terminal and at the cell body when 2nd messengers are recruited to the plasma membrane by activated receptors. After receptor-mediated endocytosis, 2nd messenger molecules continue to be recruited to the internalized vesicle; however, the mix of proteins differs in the nerve terminal and in the cell body. At the nerve terminal the activated pathways result in the formation of the neurotrophin signaling endosome, which includes molecules to be retrogradely transported to the cell body. When the retrograde neurotrophin signaling endosome reaches the cell body, it can recruit additional 2nd messenger molecules to finally generate the unique signal derived from the nerve terminal. We propose that the multivesicular body observed in vivo functions as an endosome carrier vehicle or retrosome. This retrosome enables the mix of signaling molecules recruited at the terminal to be transported intact to the cell body. This will allow the cell body to receive a snapshot of the events occurring at the nerve terminal at the time the retrosome is formed.