The basic helix-loop-helix/PAS (bHLH/PAS) family of proteins regulates transcriptional responses during development and in response to environmental stimuli. bHLH/PAS factors act as heterodimers, and genetic and biochemical data indicate that multiple heterodimeric combinations are found in vivo to regulate hypoxic gene expression. For example, HIF1alpha heterodimerizes with the highly related proteins ARNT or ARNT2 in neurons. In vivo, MOP3 interacts with CLOCK to regulate circadian rhythms; however, its role in hypoxia responses is unclear. We show here that unlike ARNT and ARNT2, MOP3 does not effectively form HIF-1 complexes or restore HIF-1 target gene expression in response to low oxygen when expressed in Arnt(-/-) ES cells. Furthermore, Mop3(-/-) day 9.5 embryos exhibit no angiogenic defects as shown for Arnt(-/-), Hif1alpha(-/-), and Hif2alpha(-/-) embryos. Therefore, by a variety of criteria, we show that MOP3 has little if any role in the regulation of hypoxia responses in vivo. (C) 2002 Elsevier Science (USA).