Neurotrophins: roles in neuronal development and function

Abstract

Neurotrophins regulate development, maintenance, and function of vertebrate nervous systems. Neurotrophins activate two different classes of receptors, the Trk family of receptor tyrosine kinases and p75NTR, a member of the TNF receptor superfamily. Through these, neurotrophins activate many signaling pathways, including those mediated by ras and members of the cdc-42/ras/rho G protein families, and the MAP kinase, PI-3 kinase, and Jun kinase cascades. During development, limiting amounts of neurotrophins function as survival factors to ensure a match between the number of surviving neurons and the requirement for appropriate target innervation. They also regulate cell fate decisions, axon growth, dendrite pruning, the patterning of innervation and the expression of proteins crucial for normal neuronal function, such as neurotransmitters and ion channels. These proteins also regulate many aspects of neural function. In the mature nervous system, they control synaptic function and synaptic plasticity, while continuing to modulate neuronal survival.

Figure 1

Schematic diagram of Trk receptor-mediated signal transduction pathways. Binding of neurotrophins to Trk receptors leads to the recruitment of proteins that interact with specific phosphotyrosine residues in the cytoplasmic domains of Trk receptors. These interactions lead to the activation of signaling pathways, such as the Ras, phosphatidylinositol-3-kinase (PI3k), and phospholipase C (PLC)-γ pathways, and ultimately result in activation of gene expression, neuronal survival, and neurite outgrowth (see text for detailed discussions and abbreviations). The nomenclature for tyrosine residues in the cytoplasmic domains of Trk receptors are based on the human sequence for TrkA. In this diagram, adaptor proteins are red, kinase green, small G proteins blue, and transcription factors brown.

Figure 2

Schematic diagram of p75NTR-mediated signal transduction pathways. P75NTR interacts with proteins, including TRAF6, RhoA, NRAGE (neurotrophin receptor-interacting MAGE homologue), SC-1, and NRIF, and regulates gene expression, the cell cycle, apoptosis, mitogenic responses, and growth cone motility. Binding of neurotrophins to p75NTR has also been shown to activate the Jun kinase pathway, which can be inhibited by activation of the Ras-phosphatidylinositol-3-kinase (PI3K) pathway by Trk receptors. Similar to Figure 1, adaptor proteins are red, kinase green, small G proteins blue, and transcription factors brown. (See text for abbreviations.)

Figure 3

Summary of survival functions of neurotrophins in the peripheral nervous system. This diagram illustrates various components in the peripheral nervous system, including sensory ganglia, sympathetic ganglia, and enteric neurons. Only ligands or receptors with definitive loss of function phenotype are indicated in this figure. Ligands are indicated in italics and receptors are indicated in bold italics. (See text for abbreviations.)