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

Yzaguirre, Amanda D.; Padmanabhan, Arun; Groh, Eric D. de; Engleka, Kurt A.; Li, Jun; Speck, Nancy A.; Epstein, Jonathan A.

doi:10.7554/elife.07780

Cited by 17 publications

(14 citation statements)

References 61 publications

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“…During normal coronary vascularization, a number of endocardial progenitors arrive on the heart wall through the process of budding, which initially forms round structures termed blood islands (Hutchins et al, 1988; Red-Horse et al, 2010; Yzaguirre et al, 2015). Blood islands are normally found on the central portion of the ventral heart where endocardial migration is most pronounced.…”

Section: Resultsmentioning

confidence: 99%

Alternative Progenitor Cells Compensate to Rebuild the Coronary Vasculature in Elabela- and Apj-Deficient Hearts

Sharma

Ford

et al. 2017

Developmental Cell

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SUMMARY Organogenesis during embryonic development occurs through the differentiation of progenitor cells. This process is extraordinarily accurate, but the mechanisms ensuring high fidelity are poorly understood. Coronary vessels of the mouse heart derive from at least two progenitor pools, the sinus venosus and endocardium. We find that the ELABELA (ELA)-APJ signaling axis is only required for sinus venosus-derived progenitors. Because they do not depend on ELA-APJ, endocardial progenitors are able to expand and compensate for faulty sinus venosus development in Apj mutants, leading to normal adult heart function. An upregulation of endocardial SOX17 accompanied compensation in Apj mutants, which was also seen in Ccbe1 knockouts, indicating that the endocardium is activated in multiple cases where sinus venosus angiogenesis is stunted. Our data demonstrate that by diversifying their responsivity to growth cues, distinct coronary progenitor pools are able to compensate for each other during coronary development, thereby providing robustness to organ development.

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Section: Resultsmentioning

confidence: 99%

Alternative Progenitor Cells Compensate to Rebuild the Coronary Vasculature in Elabela- and Apj-Deficient Hearts

Sharma

Ford

et al. 2017

Developmental Cell

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“…The protein product of the NF1 gene, neurofibromin, is essential for embryonic cardiac valve formation and the study of mouse models has indicated that neurofibromin loss leads to cardiovascular lethality during early embryonic development; Nf1 regulation of Ras in the developing endothelium is required for regular development of endocardial cushions and the ventricular myocardium (Gitler et al 2003; Ismat et al 2006; Xu et al 2009; Bajaj et al 2012; Yzaguirre et al 2015). Haploinsufficiency for both NF1 and ADAP2 may contribute either cooperatively or additively to the increased frequency of heart defects in patients with NF1 microdeletions.…”

Section: Co-deleted Genes With the Potential To Influence The Clinicamentioning

confidence: 99%

Emerging genotype–phenotype relationships in patients with large NF1 deletions

2017

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The most frequent recurring mutations in neurofibromatosis type 1 (NF1) are large deletions encompassing the NF1 gene and its flanking regions (NF1 microdeletions). The majority of these deletions encompass 1.4-Mb and are associated with the loss of 14 protein-coding genes and four microRNA genes. Patients with germline type-1 NF1 microdeletions frequently exhibit dysmorphic facial features, overgrowth/tall-for-age stature, significant delay in cognitive development, large hands and feet, hyperflexibility of joints and muscular hypotonia. Such patients also display significantly more cardiovascular anomalies as compared with patients without large deletions and often exhibit increased numbers of subcutaneous, plexiform and spinal neurofibromas as compared with the general NF1 population. Further, an extremely high burden of internal neurofibromas, characterised by >3000 ml tumour volume, is encountered significantly, more frequently, in non-mosaic NF1 microdeletion patients than in NF1 patients lacking such deletions. NF1 microdeletion patients also have an increased risk of malignant peripheral nerve sheath tumours (MPNSTs); their lifetime MPNST risk is 16–26%, rather higher than that of NF1 patients with intragenic NF1 mutations (8–13%). NF1 microdeletion patients, therefore, represent a high-risk group for the development of MPNSTs, tumours which are very aggressive and difficult to treat. Co-deletion of the SUZ12 gene in addition to NF1 further increases the MPNST risk in NF1 microdeletion patients. Here, we summarise current knowledge about genotype–phenotype relationships in NF1 microdeletion patients and discuss the potential role of the genes located within the NF1 microdeletion interval whose haploinsufficiency may contribute to the more severe clinical phenotype.

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“…Evidence suggests that the blood cells within these structures arise because the endocardium is hemogenic and able to differentiate into hematopoietic cells (37, 38). Blood island formation and their hemogenic activity is negatively regulated by sVegfr1, TgfbrIII, and the RasGap activity of Nf1 (39–41). These studies showed the sinus venosus and endocardium to be sources for coronary endothelial cells and proposed a migratory pathway by which they populate the heart.…”

Section: Coronary Vessel Progenitor Cells and Their Differentiation Pmentioning

confidence: 99%

Coronary Artery Development: Progenitor Cells and Differentiation Pathways

Sharma

Chang

Red‐Horse

2017

Annu. Rev. Physiol.

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Coronary artery disease (CAD) is the number one cause of death worldwide and involves the accumulation of plaques within the artery wall that can occlude blood flow to the heart and cause myocardial infarction. The high mortality associated with CAD makes the development of medical interventions that repair and replace diseased arteries a high priority for the cardiovascular research community. Advancements in arterial regenerative medicine could benefit from a detailed understanding of coronary artery development during embryogenesis and of how these pathways might be reignited during disease. Recent research has advanced our knowledge on how the coronary vasculature is built and revealed unexpected features of progenitor cell deployment that may have implications for organogenesis in general. Here, we highlight these recent findings and discuss how they set the stage to interrogate developmental pathways during injury and disease.

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

Cited by 17 publications

References 61 publications

Alternative Progenitor Cells Compensate to Rebuild the Coronary Vasculature in Elabela- and Apj-Deficient Hearts

Alternative Progenitor Cells Compensate to Rebuild the Coronary Vasculature in Elabela- and Apj-Deficient Hearts

Emerging genotype–phenotype relationships in patients with large NF1 deletions

Coronary Artery Development: Progenitor Cells and Differentiation Pathways

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