Decision letter: Loss of neurofibromin Ras-GAP activity enhances the formation of cardiac blood islands in murine embryos

Abstract

Messages are carried from the surface of a cell to the cell’s nucleus in order to regulate various processes such as how often the cell will divide. The Ras-signaling pathway carries some of these messages. A gene called Nf1 encodes a protein in this pathway that deactivates another protein called Ras when the message is no longer required. If a mutation in Nf1 prevents it from deactivating Ras, the pathway becomes hyperactivated. In humans, this results in a disorder called Neurofibromatosis type I, which is characterized by tumors that affect many parts of the body. When the expression of Nf1 is turned off in mice, the mice die as embryos because of cardiac defects. But a mouse in which Nf1 has been turned off in specific organs or tissues other than the heart can survive, and these mice are used to model Neurofibromatosis type I and to help to identify potential treatments. Yzaguirre et al. have now identified new roles for Nf1 during embryonic development. In the embryo, blood cells originate from the cells lining the blood vessels. The experiments revealed that, when the Nf1 gene was mutated in mice, fewer blood cells formed from the lining of the major blood vessel that leaves the embryonic heart. In contrast, these mutant mice formed more structures called cardiac blood islands than a normal mouse. These structures line the heart, and have the potential to generate new blood cells for the heart to pump. These results shed new light on how blood is originally formed from the lining of the heart and blood vessels, and show that Ras signaling must be tightly regulated to maintain normal blood development in the embryo. Furthermore, Yzaguirre et al. demonstrated that this excessive formation of cardiac blood islands resulted specifically from the loss of Nf1’s role in the Ras-signaling pathway. This was achieved by using gene targeting to generate a mouse that expresses Nf1 with a minor change that affects only the protein’s interaction with Ras. In the future, this new strain of mouse will be a useful tool in determining if specific aspects of Neurofibromatosis type I can be attributed to loss of Nf1’s role in Ras-signaling and could therefore be treated by medicines that target this pathway.