Elsevier

Brain Research

Volume 1192, 4 February 2008, Pages 37-60
Brain Research

Review
Control of cell proliferation by neurotransmitters in the developing vertebrate retina

https://doi.org/10.1016/j.brainres.2007.04.076Get rights and content

Abstract

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 (γ-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.

Section snippets

Control of cell cycle in retinal progenitor cells: evidence for regulation by cell-extrinsic factors

The vertebrate neural retina is a complex sensory tissue, and its correct formation depends on the precise timing and coordination of multiple processes during development. These include the generation of appropriate numbers and proportions of the different retinal cell types and their organization into the classic laminar cytoarchitecture of the mature retina. The vertebrate retina is mainly comprised of six neuronal cell types (rod and cone photoreceptors, horizontal, bipolar, amacrine and

Sources of neurotransmitters in development

A key requirement in understanding the roles of neurotransmitters during retinal development is to identify the source of such neurotransmitters. At any given stage of development, the immature retina is composed of varying numbers of progenitor cells, post-mitotic cells and differentiating neurons or glia (Figs. 1A, B). Given that retinal neurogenesis begins as early as embryonic day (E)2 in the chick (Prada et al., 1991) and E11 in the mouse (Carter-Dawson and LaVail, 1979, Young, 1985), the

Mechanisms of neurotransmitter release during development

The classical mechanism of neurotransmitter release from neurons is via synaptic vesicular exocytosis. Neurotransmitters are stored in vesicles located in the presynaptic terminal. Upon stimulation these fuse transiently with the cell membrane, discharging their contents into the synaptic cleft. Neurotransmitters diffuse across the cleft to the target cell and activate the appropriate receptors. The majority of synaptic connections have yet to form at the stage of development considered here

Acetylcholine

ACh acts at ligand-gated ionotropic receptors called nicotinic (n)AChRs, and muscarinic (m)AChRs. Muscarinic AChRs are metabotropic G-protein-coupled receptors coupled either to the release of Ca2+ from IP3-sensitive intracellular stores or to adenylate cyclase (AC) and the production of cAMP. Both mAChRs and nAChRs are expressed early in various developmental systems (Vogel and Nirenberg, 1976, Laasberg et al., 1987), although precise expression data are restricted to the chick. In the chick

Neurotransmitter-activated signaling pathways in the developing retina: from second messengers to cell cycle

The evidence reviewed above demonstrates that a wide range of neurotransmitters and their receptors are present during the earliest stages of development. Understanding how these neurotransmitters are linked to specific downstream developmental consequences is a key issue and remains an important area for future research. In this section, we briefly review some of the second messengers and signaling pathways activated by these transmitters and how these pathways might potentially act upon the

Acetylcholine

Muscarinic receptor activity appears to act as a brake on retinal progenitor mitosis; almost doubling the time it takes for cells to divide (Pearson et al., 2002). Muscarinic agonists reduce proliferation and DNA synthesis in immature rat retinal cultures, while antagonists led to a small increase in proliferation, suggesting that endogenous ACh leads to a negative regulation of cellular proliferation (dos Santos et al., 2003). In the chick, exposure to muscarinic agonists or antagonists leads

Conclusions and perspectives

The control of cell proliferation in complex tissues such as the developing retina depends on an array of both cell-intrinsic and cell-extrinsic factors. Among the various environmental factors that regulate retinal development, the data reviewed here highlight an emerging role for neurotransmitters in the control of retinal progenitor cell proliferation. We have focused on the growing body of research examining the developmental expression of neurotransmitter receptors that, together with more

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