Dihydroorotate dehydrogenase (DHODH) is one of three enzymes that catalyze the six enzymatic reactions needed for de novo synthesis of pyrimidine. DHODH catalyzes the conversion of dihydroorotate to orotic acid, which is then converted to uridine monophosphate, the RNA nucleotide essential for ribosome biogenesis. There are currently no mouse models for POADS, but inhibition of DHODH by the immunosuppressant leflunomide in zebrafish completely abolished NCC, resulting in a reduction of their derivatives as well as a disruption in the jaw cartilage. Moreover, microarray analysis of leflunomide-treated zebrafish embryos showed downregulation of NCC genes. Leflunomide also caused a decrease in the self-renewal capacity of rat NC stem cells. These data suggest defects in NCC development are a potential cause of the pathogenesis of POADS.