D1-type dopamine receptors inhibit growth cone motility in cultured retina neurons: evidence that neurotransmitters act as morphogenic growth regulators in the developing central nervous system.

Abstract

Precedent exists for the early development and subsequent down-regulation of neurotransmitter receptor systems in the vertebrate central nervous system, but the function of such embryonic receptors has not been established. Here we show that stimulation of early-developing dopamine receptors in avian retina cells greatly inhibits the motility of neuronal growth cones. Neurons from embryonic chicken retinas were cultured in low-density monolayers, and their growth cones were observed with phase-contrast or video-enhanced-contrast-differential-interference-contrast (VEC-DIC) microscopy. Approximately 25% of the neurons responded to micromolar dopamine with a rapid reduction in filopodial activity followed by a flattening of growth cones and retraction of neurites. The response occurred at all ages examined (embryonic day-8 retinal neurons cultured on polylysine-coated coverslips for 1-7 days), although neurite retraction was greatest in younger cultures. Effects of dopamine on growth cone function could be reversed by haloperidol or (+)-SCH 23390, whereas forskolin elicited a response similar to dopamine; these data show the response was receptor-mediated, acting through a D1-type system, and are consistent with the use of cAMP as a second messenger. The experiments provide strong support for the hypothesis that neurotransmitters, besides mediating transynaptic signaling in the adult, may have a role in neuronal differentiation as growth regulators.

GAP-43 amino terminal peptides modulate growth cone morphology and neurite outgrowth

“…Expression of activated mutants of the (Y subunit of G, promote neurite outgrowth (Strittmatter et al, 1994a). Furthermore, ligands for G-protein-coupled receptors such as serotonin, dopamine, and thrombin induce growth cone collapse in particular cell types (Haydon et al, 1984;Lankford et al, 1988;Rodrigues and Dowling, 1990;Suidan et al, 1992). The neurite outgrowth modulating activity of both membrane-bound growth cone collapsing factors (Igarashi et al, 1993) and cell adhesion molecules (Doherty et al,199 1) can be abrogated by pertussis toxin treatment of neurons.…”

Molecular Mechanisms of Axon Growth and Guidance

“…Indeed, signals such as electrical impulses and neurotransmitters can elevate intracellular Ca 2+ and thereby affect neurite growth (e.g. Mattson & Kater 1987;Lankford et al 1988;Silver et al 1990). What is less clear is whether or not the control of intracellular Ca 2+ is an element of signal transduction used by growth-promoting proteins.…”

“…As is also the case for Ca z+, studies linking intracellular cAMP levels to regulation of neurite outgrowth have led to differing conclusions. In a number of neuronal types responding to a variety of cues, elevations of intracellular cAMP have been shown to be inhibitory to neufite growth and/or growth cone motility (Forscher et al 1987;Lankford et al 1988;Mattson et al 1988;Bixby 1989). Experiments with neural cell lines, in apparent contrast, suggest that increasing cAMP levels is stimulatory for neurite growth (Nirenberg et al 1983;Greene et al 1986).…”

Enhanced neurotransmitter release is associated with reduction of neuronal branching in a Drosophila mutant overexpressing frequenin

“…γ‐aminobutyric acid (GABA) increases the number of primary processes as well as the length and branching of neurites in embryonic chick cortical and retinal neurones grown in cultures ( Spoerri 1988). By contrast, dopamine ( Lankford et al 1988 ), acetylcholine ( Lipton et al 1988 ) and glutamate ( Mattson et al 1988 ) show inhibitory effects on elongation of retinal and hippocampal pyramidal cell neurites. In the snail Helisoma , serotonin and dopamine regulate neuronal cell geometry ( McCobb et al .…”