Ras GTPase activating proteins (RasGAPs) control the activation of Ras, a small GTP-binding protein that regulates signal transduction pathways involved in cell growth, survival, and differentiation. Inactivating mutations the RasGAP RASA1 cause a blood and lymphatic vessel (LV) disorder known as capillary malformation-arteriovenous malformation, though exactly how loss of RASA1 function contributes to LV leakage is unclear.
This week in the JCI, research led by Philip King at University of Michigan Medical School reports that LV development and function critically depends on RASA1 activity. Ablation of RASA1 in adult mice led to specific defects in lymphatic valves that impaired the efficiency of LV pumping. Valve closure tests revealed that RASA1-deficient lymphatic vessels failed to prevent back-leak across valves. Moreover, ablating RASA1 in embryos impaired LV valve development. Together, these findings support an essential role for RASA1 in both LV formation and maintenance.
The accompanying video visualizes LV responses to increases in downstream pressure. In the top panel, as pressure increases, LV valves in wildtype mice rapidly close to prevent backflow. In the bottom panel, valve failure in RASA1-deficient mice results in backflow into the upstream regions of the LV.
One of the leading factors in breast cancer-related death, is tumor recurrence despite apparently successful therapeutic intervention. Recurrent disease is linked to the presence of a minimal population of residual cancer cells that are hard to detect; therefore, little is known about these cells. In this episode, Martin Jechlinger and colleagues present several lines of evidence to show that residual cells have a distinct transcriptional profile that results in changes in metabolism and elevated ROS production. Together, these results provide a better understanding of these cells and suggest potential targeting strategies.
Invariant natural killer T (iNKT) cells are a prominent component of the liver-resident immune cell population. These cells are involved in both liver regeneration and regulation of the local immune response; however, little is known about how iNKT cells are maintained within the liver. In this episode, Xian Li reveals that stimulation of cell surface receptor OX40 induces a pyroptotic cell death in liver iNKT cells that exacerbates liver injury and inflammation. The results of this study support the OX40 pathway as a potential therapeutic target for limiting liver damage.
Mice with defects in the stem cell factor receptor Kit lack mast cells, which have been implicated in a variety of inflammatory diseases such as arthritis. There are strain-specific differences in how mast cell-deficient animals manifest model diseases, leading to questions about the role of mast cells in certain pathologies. In this episode, Peter Nigrovic and colleagues investigate differences in mast cell-deficient mice that lead to differential susceptibility to IgG-induced arthritis. Using a series of bone marrow and cell transplantation experiments, Nigrovic and coworkers reveal that marrow and stromal context determine the role of mast cells in inflammation and that megakaryocytes can directly mediate inflammation.
During Stuart Orkin’s training as a physician-scientist, he decided to focus on pediatric blood disorders as an area where disease genetics could connect directly to scientific investigations. His work in this field ultimately identified the genetic mutations responsible for thalassemia and chronic granulomatous disease. Recently, his focus has shifted toward singling out hematopoietic targets that can be exploited to treat hematological disorders, including leukemia and sickle cell disease. In this issue of the JCI, Editor at Large Ushma Neill interviews Dr. Orkin to discuss his path toward medicine and scientific research as well as the stories behind these highlights of his research career.