USP22 controls multiple signaling pathways that are essential for vasculature formation in the mouse placenta

ABSTRACT USP22, a component of the SAGA complex, is overexpressed in highly aggressive cancers, but the normal functions of this deubiquitinase are not well defined. We determined that loss of USP22 in mice results in embryonic lethality due to defects in extra-embryonic placental tissues and failure to establish proper vascular interactions with the maternal circulatory system. These phenotypes arise from abnormal gene expression patterns that reflect defective kinase signaling, including TGFβ and several receptor tyrosine kinase pathways. USP22 deletion in endothelial cells and pericytes that are induced from embryonic stem cells also hinders these signaling cascades, with detrimental effects on cell survival and differentiation as well as on the ability to form vessels. Our findings provide new insights into the functions of USP22 during development that may offer clues to its role in disease states. Highlighted Article: Global loss of the USP22 deubiquitinase, an integral subunit of the SAGA chromatin remodeler, reveals an unexpected role in the regulation of signaling cascades in endothelial and perivascular cells of the developing mouse placenta.

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