The paternally imprinted Neuronatin gene (NNAT) is initially expressed in rhombomeres and the pituitary gland and is later expressed more widely, but much less abundantly, in the central and peripheral nervous systems. The human NNAT gene maps to chromosome 20q11.23 and contains an imprinting region associated with morphological abnormalities and early neonatal lethality. Specifically, hypermethylation of the NNAT gene occurs in both myeloid and lymphoid acute pediatric leukemias and may inhibit NNAT expression. The Neuronatin protein consists of two isoforms, alpha and beta, which are the products of alternative splicing. The alpha form of the Neuronatin gene is encoded by three exons, whereas the beta form is missing the second exon. Neuronatin mRNA expression is abundant in undifferentiated PC-12 cells. Treatment of these cells with nerve growth factor (NGF), which contributes to neuronal differentiation, downregulates Neuronatin mRNA expression. NNAT (-) 1.9 PC-12 cells exhibit an increase in nigericin, rotenone and valinomcin sensitivity; NNAT transfection restores wild-type PC-12 resistance. These results suggests a potential protective role for Neuronatin against toxic insult during development.