Degradation of proteins by the ubiquitin-proteasome system (UPS) is critical for many biological processes. Copper Metabolism gene MURR1 Domain 1 (COMMD1) is a recently identified regulator of hypoxia inducible factor 1a (HIF-1a) protein degradation. As a subunit of the transcription factor hypoxia inducible factor 1 (HIF-1), HIF-1a is the major component of the cellular oxygen sensing system. In vertebrates, HIF-1 is critically involved in many aspects of development and physiology, including placental development. Recently, we demonstrated that Commd1 is essential for normal mouse placental vascularization. COMMD1 physically associates with HIF-1a and reduced COMMD1 expression leads to an increase in HIF-1a protein stability. Based on our observations we hypothesize that Commd1 is a critical regulator of HIF-1 function in placental and vascular development. Here we aim to elucidate the role of Commd1 in HIF-1 signaling during mouse embryogenesis. In the key objectives we will: 1. Elucidate the biochemical mechanisms of the regulation of HIF-1 activity by COMMD1 2. Identify the physiological roles of murine Commd1 during the development of the embryonic and extra-embryonic tissues 3. Asses the role of murine Commd1 in regulating Hif-1 activity during placental development in vitro. Towards these purposes we have developed unique mouse and cell culture models, that will allow us to delineate the physiological and biochemical pathways responsible for the finetuning of Hif-1 activity. A better understanding of the mechanism by which COMMD1 mediates HIF-1a stability will be essential to unravel the biological function of COMMD1 in relation to HIF1 activity, and will contribute to our general understanding of the regulation of protein degradation.