ROLE OF CYCLIC AMP IN DEVELOPING BRAIN

Abstract

Adenosine 3',5'-cyclic monophosphate appears to be one of the important factors in the induction of neural tissue as well as in the regulation of several differentiated functions. However, the expression of many of the differentiated functions can be increased by agents which do not change the intracellular level of cyclic AMP, indicating that the regulation of some of the neuronal properties involves more than one mode, one of which is the change in level of cyclic AMP. The expression of morphological and some biochemical differentiation appears to be independently regulated, since one can express in the absence of others. The increase in the level of cyclic AMP binding proteins may be one of the important intracellular mechanisms of maintaining high cyclic AMP level during differentiation, since the protein bound cyclic AMP is resistant to the enzymatic hydrolysis. The increase in the level of binding protein is also associated with the specific changes (increase and decrease) in cyclic AMP-dependent and cyclic AMP-independent phosphorylation activity. Cyclic AMP in some way inhibits the expression of certain genes, whereas it increases the expression of others. We have identified those gene products which are increased, those which are decreased, and those which remain unaltered during cyclic AMP-induced differentiation of neuroblastoma cells in culture. Cyclic AMP in some way must turn off cell division at a precise time during development. Indeed, the synthesis and phosphorylation of Hj-histone which are linked with cell proliferation are markedly decreased in cyclic AMP-induced differentiated neuroblastoma cells which have stopped cell division. Nerve growth factor (NGF) also induces certain differentiated functions in developing nervous tissue similar to that produced by cyclic AMP. NGF has shown to increase the cyclic AMP level in certain systems. However, the relationship between cyclic AMP and NGF remains to be defined. The exact mechanisms of cyclic AMP-effect during differentiation are still unknown. Cyclic GMP does not appear to be involved in the mechanism of neural induction or in further differentiation. One fundamental question remains obscure. After neural induction what factor(s) initiate the separation of glial and nerve cells, and various types of nerve cell?