ReviewControl of cell proliferation by neurotransmitters in the developing vertebrate retina
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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