Nitric oxide triggers a switch to growth arrest during differentiation of neuronal cells

• Published in: Nature (London) 1995-05, Vol.375 (6526), p.68-73
• Main Authors: Peunova, Natalia, Enikolopov, Grigori
• Format: Article
• Language: English
• Subjects: Amino Acid Oxidoreductases - antagonists & inhibitors; Amino Acid Oxidoreductases - biosynthesis; Amino Acid Oxidoreductases - genetics; Animals; Arginine - analogs & derivatives; Arginine - pharmacology; Biological and medical sciences; Cell Differentiation - genetics; Cell Differentiation - physiology; Cell division; Cell Division - genetics; Cell Division - physiology; Cellular biology; Development. Senescence. Regeneration. Transplantation; DNA - biosynthesis; Enzyme Induction; Evidence; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; letter; Medical research; multidisciplinary; Mutation; Nerve Growth Factors - physiology; Neurites; Neurons; Neurons - cytology; Neurons - drug effects; NG-Nitroarginine Methyl Ester; Nitric oxide; Nitric Oxide - physiology; Nitric Oxide Synthase; PC12 Cells; Rats; Science; Science (multidisciplinary); Second Messenger Systems; Vertebrates: nervous system and sense organs
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/375068a0

ARREST of cell division is a prerequisite for cells to enter a program of terminal differentiation. Mitogenesis and cytostasis of neuronal cell precursors can be induced by the same or by different growth or trophic factors 1á€-9 . Response of PC12 cells to nerve growth factor (NGF) involves a proliferative phase that is followed by growth arrest and differentiation. Here we present evidence that the cytostatic effect of NGF is mediated by nitric oxide (NO), a second messenger molecule with both para- and autocrine properties that can diffuse freely and act within a restricted volume 10á€-14 . We show that NGF induces different forms of nitric oxide synthase (NOS) in neuronal cells, that nitric oxide (NO) acts as a cytostatic agent in these cells, that inhibition of NOS leads to reversal of NGF-induced cytostasis and thereby prevents full differentiation, and that capacity of a mutant cell line to differentiate can be rescued by exogenous NO. We suggest that induction of NOS is an important step in the commitment of neuronal precursors and that NOS serves as a growth arrest gene, initiating the switch to cytostasis during differentiation.