Control of cell proliferation by neurotransmitters in the developing vertebrate retina

In the developing vertebrate retina, precise coordination of retinal progenitor cell proliferation and cell-cycle exit is essential for the formation of a functionally mature retina. Unregulated or disrupted cell proliferation may lead to dysplasia, retinal degeneration or retinoblastoma. Both cell-intrinsic and -extrinsic factors regulate the proliferation of progenitor cells during CNS development. There is now growing evidence that in the developing vertebrate retina, both slow and fast neurotransmitter systems modulate the proliferation of retinal progenitor cells. Classic neurotransmitters, such as GABA (gamma-amino butyric acid), glycine, glutamate, ACh (acetylcholine) and ATP (adenosine triphosphate) are released, via vesicular or non-vesicular mechanisms, into the immature retinal environment. Furthermore, these neurotransmitters signal through functional receptors even before synapses are formed. Recent evidence indicates that the activation of purinergic and muscarinic receptors may regulate the cell-cycle machinery and consequently the expansion of the retinal progenitor pool. Interestingly, GABA and glutamate appear to have opposing roles, inducing retinal progenitor cell-cycle exit. In this review, we present recent findings that begin to elucidate the roles of neurotransmitters as regulators of progenitor cell proliferation at early stages of retinal development. These studies also raise several new questions, including how these neurotransmitters regulate specific cell-cycle pathways and the mechanisms by which retinal progenitor cells integrate the signals from neurotransmitters and other exogenous factors during vertebrate retina development.