Mechanism of Action of Nerve Growth Factor and Cyclic AMP on Neurite Outgrowth in Embryonic Chick Sensory Ganglia: Demonstration of Independent Pathways of Stimulation

Abstract

The suggested role of adenosine 3':5'-cyclic monophosphate as the "second messenger" in the neurite outgrowth from chick embryonic sensory ganglia mediated by nerve growth factor was examined. Although N',02-dibutyryl adenosine 3':5'-cyclic monophosphate induces fiber outgrowth at concentrations of 1-5 mM, this response is morphologically distinct from that produced by nerve growth factor, is pH dependent, is mimicked by sodium butyrate, and does not occur in sympathetic ganglia. In addition, nerve growth factor does not alter the amounts of intracellular cyclic AMP during incubations up to 24 hr and does not stimulate adenylate cyclase in broken-cell preparations. Addition of theophylline, an inhibitor of phosphodiesterase, causes increases in intracellular levels of cyclic AMP but does not affect fiber outgrowth. These observations indicate that the nerve growth factor response is not mediated through cyclic AMP and that stimulation of sensory ganglia by exogenous cyclic AMP derivatives is probably of limited physiological significance. These findings are also compatible with the developing hypothesis, based on structural similarities, that nerve growth factor and insulin exert their effects on their respective responsive tissues by related mechanisms.

POTENTIATION OF THE NGF-MEDIATED NERVE FIBER OUTGROWTH BY GINSENOSIDE Rb1 IN ORGAN CULTURES OF CHICKEN DORSAL ROOT GANGLIA

“…a dense halo of long, straight nerve fibers, was obtained with 0.8 to 1.6 nM 2.5 S NGF. Supraoptimal doses (index [5][6][7][8] resulted in a dense outgrowth, at which time the length of the individual fibers was progres sively reduced. The outgrowth with suboptimal doses was sparse (0.1-0.8 nM) (Fig.…”

The effect of cyclic AMP on neuritic outgrowth in explant cultures of developing chick olfactory epithelium

“…The involvement of cyclic nucleotides in the regulation of cell growth and differentiation has been a focus of research since 1971 when N6,2'-0-dibutyryl-adenosine cyclic monophosphate (dbcAMP) was shown to slow proliferation and induce a change in cell shape in Chinese hamster ovary cells (Hsie and Puck, 1971) or fibroblasts (Johnson, Friedman, and Pastan, 1971) in culture. In cells of neural origin, treatment with CAMP, its derivatives, or with phosphodiesterase (PDE) inhibitors also slowed proliferation and caused cells to express morphological characteristics of the differentiated state; i.e., neural cells expressed neuritic processes (e.g., Frazier, Ohlendorf, Boyd, Aloe, Johnson, Ferrendelli, and Bradshaw, 1973;Furmanski, Silverman, and Lubin, 1971;Haas, Hier, Arnason, and Young, 1972;Hier, Arnason, and Young, 1972;Prasad and Hsie, 1971;Roisen, Murphy, Pichichero, and Braden, 1972;Shapiro, 1973;Werner, Peterson, and Shuster, 1971). Changes in the cytoskeleton, namely a significant increase in the numbers of aligned microtubules and microfilaments, are thought to be responsible for dbcAMP-induced changes in cell shape in neural cells (Klier, Schubert, and Heinemann, 1975).…”

cAMP analogs promote survival and neurite outgrowth in cultures of rat sympathetic and sensory neurons independently of nerve growth factor.

“…However, the effects of cAMP analogs and NGF on rat PC12 cell surface morphology (16) and neurite outgrowth from both PC12 cells (17)(18)(19) and embryonic chicken sensory ganglia (20) suggest divergent pathways of action.…”

“…13). In this regard, various groups (14)(15)(16)(17)(18)(19)(20) have reported that cAMP analogs and NGF have both synergistic and differential actions on NGF-responsive cells. cAMP analogs have been reported to modulate the phosphorylation of a similar group of proteins, as does NGF (14, 15).…”