Abstract
Type I neurofibromatosis (NF1) is caused by mutations in the NF1 gene encoding neurofibromin. Neurofibromin exhibits Ras GTPase activating protein (Ras-GAP) activity that is thought to mediate cellular functions relevant to disease phenotypes. Loss of murine Nf1 results in embryonic lethality due to heart defects, while mice with monoallelic loss of function mutations or with tissue-specific inactivation have been used to model NF1. Here, we characterize previously unappreciated phenotypes in Nf1-/- embryos, which are inhibition of hemogenic endothelial specification in the dorsal aorta, enhanced yolk sac hematopoiesis, and exuberant cardiac blood island formation. We show that a missense mutation engineered into the active site of the Ras-GAP domain is sufficient to reproduce ectopic blood island formation, cardiac defects, and overgrowth of neural crest-derived structures seen in Nf1-/-embryos. These findings demonstrate a role for Ras-GAP activity in suppressing the hemogenic potential of the heart and restricting growth of neural crest-derived tissues.
Highlights
NF1 is a common human disorder characterized by benign and malignant tumors of neural crest origin, pigmentation defects, learning disorders, cardiovascular abnormalities and a wide spectrum of other abnormalities including a predilection for leukemia and vascular defects (Cichowski and Jacks, 2001; Friedman et al, 2002)
Since many fetal liver progenitors in the midgestation embryo originate in the yolk sac (Lux et al, 2008), we examined the number of erythroid/myeloid progenitors (EMPs) in the yolk sac of E10.5 Nf1-deficient embryos
In contrast to the increase in EMPs observed in the yolk sac, CD31+ Kit+ Runx1+ hematopoietic cluster cells were decreased in the dorsal aortas of E10.5 Nf1-deficient embryos (Figure 1C,D)
Summary
NF1 is a common human disorder characterized by benign and malignant tumors of neural crest origin, pigmentation defects, learning disorders, cardiovascular abnormalities and a wide spectrum of other abnormalities including a predilection for leukemia (especially juvenile myelomonocytic leukemia, [JMML]) and vascular defects (Cichowski and Jacks, 2001; Friedman et al, 2002). Some of these phenotypes, including JMML and vascular defects, are shared by patients with related disorders associated with activation of the Ras signaling pathway, which together have been termed the ’RAS-opathies’ (Rauen et al, 2010).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
