FIGURE 5.

Proposed mechanism underlying the arginine-deficient phenotype in mice. Arginine is the precursor for NO, polyamines, and creatine synthesis, and regulates ADP-ribosylation, but these molecules do not mediate the developmental impairment of F/A2 mice. The somatotropic (GH/IGF1) axis does not function properly in arginine-deficient mice, but although GH supplementation increases Igf1 mRNA concentration to wild-type values, it cannot restore growth. Arginine deficiency, finally, does not block mTORC1 phosphorylation-dependent signaling, but does activate the stress kinase GCN2 in neonatal and suckling F/A2 mice. The sole activation of the GCN2-mediated integrated stress response is apparently necessary and sufficient to block growth in a highly distinctive way.