Heme deficiency interferes with the Ras-mitogen-activated protein kinase signaling pathway and expression of a subset of neuronal genes.

Defective heme synthesis in mammals has been suspected of causing neuropathy associated with porphyrias and lead poisoning. To determine the molecular action of heme in neuronal cells, we examined the effect of the inhibition of heme synthesis on nerve growth factor (NGF) signaling in PC12 cells. We found that the inhibition of heme synthesis by succinyl acetone interferes with NGF-induced neurite outgrowth in PC12 cells. Furthermore, we show that heme deficiency obliterates the activation of the signaling intermediates of the Ras-mitogen-activated protein kinase signaling pathway and its downstream target, the transcription activator cyclic AMP response element-binding protein. Strikingly, microarray expression analysis shows that the inhibition of heme synthesis selectively diminishes the induction of expression of a subset of neuron-specific genes by NGF, such as Ras and neurofilament proteins, whereas NGF induces the expression of several major classes of neuronal genes that encode regulatory and structural proteins at three days after induction. Our data provide insights into how heme deficiency interferes with NGF signaling and abrogates programs of neuronal gene expression, thus ultimately causing defective neuronal functions.