Noradrenaline and cyclic AMP—independent growth stimulation in newt limb blastemata

Abstract

Adult newts regenerate functional limbs after amputation. This process normally depends on the trophic influence of nerves on the regenerating limbs, particularly in the early stages before differentiation of the regeneration blastema, when it stimulates growth by maintaining high rates of macromolecular synthesis. The sequence of biochemical events involved is unknown, but it has been suggested that intracellular cyclic AMP may be a second messenger within the blastema. Many studies have indicated that the neural agent(s) involved might be protein. The recent finding that blastemata contain high levels of catecholamines, however, has implicated noradrenaline (NA) as the neurotrophic agent, and suggested that it works via stimulation of beta-adrenergic receptors on the blastemal cells, thereby raising the intracellular concentrations of cyclic AMP. To test this hypothesis we studied the ability of NA alone and in combination with alpha-and beta-adrenergic antagonists to increase cyclic AMP levels and to mimic the effects of nerves by maintaining high rates of protein synthesis and high mitotic indices (MI) in denervated blastemata in organ culture. We find that although NA raises cyclic AMP levels through a beta-adrenergic effect, it does not maintain high rates of protein synthesis or high MI in cultured blastemata. It is unlikely therefore, that this hypothesis applies.

Nerve Dependence: From Regeneration to Cancer

“…Importantly, the release of transferrin (Mescher et al, 1997), neuregulin (Wang et al, 2000) and the neurotransmitter substance P (Smith et al, 1995) by nerve endings in the regenerating blastema has been demonstrated, and can partially rescue the denervated blastema and support regeneration. In contrast, early investigations have shown that acetylcholine and its receptors (Drachman and Singer, 1971), as well as noradrenaline (Rathbone et al, 1980), were not involved in stimulating blastema cells. However, a recent investigation in heart regeneration has shown that cholinergic nerves are necessary to cardiomyocyte proliferation and that the pharmacological inhibition of muscarinic acetylcholine receptors can block heart regeneration (Mahmoud et al, 2015).…”