Signaling by Notch receptors is an essential cell-cell communication mechanism essential for developmental patterning throughout evolution, controlling cell fate decision, cellular differentiation, as well as morphogenesis and growth of multiple organ systems. In the vascular system, Notch signaling coordinates critical steps of angiogenic blood vessel growth during development and tumor formation. Even subtle differences in endothelial Notch activity have profound consequences for the vascular morphogenesis - yet the mechanisms that balance endothelial Notch responses are poorly understood.
In a recent paper published in Science, an international team of scientists led by Max Planck researcher Michael Potente identified a novel way to regulate this pathway in the blood vasculature. This mechanism involves a protein called USP10, an enzyme (deubiquitinase) that cleaves ubiquitin (chains) from its protein substrates. The researchers showed that USP10 interacts with the activated NOTCH1 (NICD1) to remove ubiquitin molecules that otherwise mark this short-lived receptor for degradation. Combining genetic, biochemical and transcriptome analyses, they demonstrated that USP10 affects the dynamics of Notch signaling and that its inactivation reduces the amplitude and duration of endothelial Notch responses.
The team, which included several members of the Cardiopulmonary Institute (CPI), further illustrated that this mechanism is relevant for angiogenic blood vessel growth during which dynamic changes in Notch activity determine the specification and positioning of endothelial cells. This study thereby identified USP10 as a regulatory component of the Notch pathway, which fine-tunes Notch-dependent vessel branching morphogenesis. USP10, itself regulated by metabolic and cellular stress signals, might allow endothelial cells to adjust Notch responses to changing tissue environments.
Figure | Blood vasculature in retinas of control and endothelial-specific Notch gain-of-function mice showing impaired vascular growth when the Notch pathway is aberrantly activated. Endothelial cells were fluorescently labeled with nuclear (green) and cytoplasmic (blue) markers. Endothelial cells with ectopic activation of the Notch pathway also express a red-fluorescent marker. A, artery; V, vein.