A multifunctional PKS-NRPS megasynthetase in nematodes produces divergent signaling molecules that control different developmental arrests.

To maximize their reproductive success, nematodes not only must arrest their development in response to adverse growth conditions but also must quickly recover if conditions improve. However, the molecular signals that coordinate these transitions remain poorly understood. Here, we show that a hybrid polyketide synthase (PKS)-nonribosomal peptide synthetase (NRPS) expressed in the canal-associated neurons (CANs) is a central regulator of multiple developmental arrest programs, including starvation-induced larval arrest and dauer development. Using unbiased, comparative metabolomics in the predatory nematode Pristionchus pacificus, we show that this PKS-NRPS assembly line produces a suite of secondary metabolites, including a family of hybrid polyketide-nonribosomal peptides known as the nemamides, the related nemaketides, and a family of ascarylose-modified polyketides that we term ascarenes. Depending on the starter unit that is loaded onto the assembly line, the PKS-NRPS megasynthetase can produce dramatically different downstream products. Genetic analysis of the assembly line suggests that the nemamides promote recovery from starvation-induced larval arrest, while the ascarenes inhibit dauer development. Our work demonstrates that the PKS-NRPS assembly line serves as a signaling hub in the CANs, producing multiple signaling molecules that control different developmental events.