Regulation of neuronal survival and death by extracellular signals during development

Abstract

Cell death is a prominent feature of the developing vertebrate nervous system, affecting neurons, glial cells and their progenitors. The most extensively studied and best understood phase of cell death occurs in populations of neurons shortly after they begin establishing connections with other neurons and/or non-neural tissues. This phase of cell death makes appropriate adjustments to the relative sizes of interconnected groups of neurons and matches the size of neuronal populations that innervate non-neural tissues to the optimal requirements of these tissues. The fate of neurons during this period of development is regulated by a variety of secreted proteins that either promote survival or bring about cell death after binding to receptors expressed on the neurons. These proteins may be derived from the targets the neurons innervate, the afferents they receive or from associated glial cells, or they may be secreted by the neurons themselves. In this review, I will outline the established and emerging principles that modulate neuronal number in the developing nervous system.

Fig. 1. Schematic illustration of the routes by which neurotrophic factors influence neuronal survival. Three groups of interconnected neurons, A, B and C, are shown. Group B neurons obtain neurotrophic factors from four sources: (i) from target cells or neurons [group A neurons secrete this neurotrophic factor (red dots) which binds to receptors on the axon terminals of neurons B, and is internalized and retrogradely transported (direction of red arrows) to the cell bodies of group A neurons]; (ii) from intermediate target cells or glial cells associated with the axons of neurons B (this neurotrophic factor is represented by the blue dots and is retrogradely transported in the direction of the blue arrows); (iii) from afferents [this neurotrophic factor (green dots) is synthesized in the cell bodies of group C neurons and is anterogradely transported along the axons of these neurons (direction of green arrows) to be released from their terminals and bind to receptors on the cell bodies or dendrites of group B neurons]; and (iv) via an autocrine route (this neurotrophic factor is represented by the purple dots).