A plastid-derived signal plays an important role in the coordinated expression of both nuclear-and chloroplast-localized genes that encode photosynthesis-related proteins. Arabidopsis GUN (genomes uncoupled) loci have been identified as components of plastid-to-nucleus signal transduction. Unlike wild-type plants, gun mutants have nuclear Lhcb1 expression in the absence of chloroplast development. We observed a synergistic phenotype in some gun double-mutant combinations, suggesting there are at least two independent pathways in plastid-to-nucleus signal transduction. There is a reduction of chlorophyll accumulation in gun4 and gun5 mutant plants, and a gun4gun5 double mutant shows an albino phenotype. We cloned the GUN5 gene, which encodes the ChlH subunit of Mg-chelatase. We also show that gun2 and gun3 are alleles of the known photomorphogenic mutants, hy1 and hy2, which are required for phytochromobilin synthesis from heme. These findings suggest that certain perturbations of the tetrapyrrole biosynthetic pathway generate a signal from chloroplasts that causes transcriptional repression of nuclear genes encoding plastid-localized proteins. The comparison of mutant phenotypes of gun5 and another Mg-chelatase subunit (ChlI) mutant suggests a specific function for ChlH protein in the plastid-signaling pathway.A number of components required for plastid structure and development are encoded by the nuclear genome. There is a considerable body of evidence that suggests that the proper and timely expression of these genes depends in part on the functional state of the chloroplast. For example, nuclear mutations that result in developmentally arrested chloroplasts also result in the reduced expression of nuclear-localized photosynthetic genes (1). These results tie the functional state of the chloroplast to nuclear function and suggest that the chloroplast signals the nucleus in a retrograde fashion (2).Such retrograde signaling between chloroplast and nucleus has been studied primarily by using carotenoid-deficient plants induced either by mutations or by carotenoid biosynthesis inhibitors such as Norflurazon (Nf; refs. 3 and 4). Carotenoids prevent the production of reactive oxygen species by excited triplet states of chlorophyll. Carotenoid-deficient plants thus suffer a rapid photooxidation of most chloroplast components under intense light. Although most nuclear-encoded cytoplasmic enzymes are present at normal levels in photooxidatively damaged plants, a small set of nuclear-encoded chloroplast enzymes is absent (3, 4). Accordingly, it was hypothesized that plastids send an unknown signal(s) to the nucleus that regulates the expression of a small subset of nuclear-localized photosynthetic genes (2, 5).The molecular nature of the plastid signal(s) and the mechanism by which it is relayed to the nucleus remain ambiguous. Although both plastid transcription and translation are necessary for the production of the plastid signal (4, 6), the plastid signal is not a direct translational product of a plastid gene. Lig...