Advertisement
JOURNAL ARTICLES
Neurofibromin modulation of ras activity is required for normal endocardial-mesenchymal transformation in the developing heart
M.M. Lakkis, J.A. Epstein
Development 1998 125: 4359-4367;

Summary

Endocardial cushions are the precursors of the cardiac valves and form by a process of epithelial-mesenchymal transformation. Secreted growth factors from myocardium induce endocardial cells to transform into mesenchyme and invade the overlying extracellular matrix. Here, we show that the product of the Nf1 neurofibromatosis gene is required to regulate this event. In the absence of neurofibromin, mouse embryo hearts develop overabundant endocardial cushions due to hyperproliferation and lack of normal apoptosis. Neurofibromin deficiency in explant cultures is reproduced by activation of ras signaling pathways, and the Nf1(−/−) mutant phenotype is prevented by inhibiting ras in vitro. These results indicate that neurofibromin normally acts to modulate epithelial-mesenchymal transformation and proliferation in the developing heart by down regulating ras activity.

REFERENCES

    1. Abuelo D. N.,
    2. Meryash D. L.
    (1988) Neurofibromatosis with fully expressed Noonan syndrome. Am. J. Med. Genet 29, 937–941
    OpenUrlCrossRefPubMedWeb of Science
    1. Baldwin H. S.,
    2. Shen H. M.,
    3. Yan H. C.,
    4. DeLisser H. M.,
    5. Chung A.,
    6. Mickanin C.,
    7. Trask T.,
    8. Kirschbaum N. E.,
    9. Newman P. J.,
    10. Albelda S. M.,
    11. et al.
    (1994) Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31): alternatively spliced, functionally distinct isoforms expressed during mammalian cardiovascular development. Development 120, 2539–2553
    OpenUrlAbstract/FREE Full Text
    1. Ballester R.,
    2. Marchuk D.,
    3. Boguski M.,
    4. Saulino A.,
    5. Letcher R.,
    6. Wigler M.,
    7. Collins F.
    (1990) The NF1 locus encodes a protein functionally related to mammaliean GAP and yeast IRA proteins. Cell 63, 851–859
    OpenUrlCrossRefPubMedWeb of Science
    1. Bernards A.
    (1995) Neurofibromatosis type 1 and Ras-mediated signaling: filling in the GAPs. Biochim. et Biophy. Acta 1242, 43–59
    OpenUrlPubMed
    1. Bollag G.,
    2. Clapp D. W.,
    3. Shih S.,
    4. Adler F.,
    5. Zhang Y. Y.,
    6. Thompson P.,
    7. Lange B. J.,
    8. Freedman M. H.,
    9. McCormick F.,
    10. Jacks T.,
    11. Shannon K.
    (1996) Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nature Genet 12, 144–148
    OpenUrlCrossRefPubMedWeb of Science
    1. Brannan C. I.,
    2. Perkins A. S.,
    3. Vogel K. S.,
    4. Ratner N.,
    5. Nordlund M. L.,
    6. Reid S. W.,
    7. Buchberg A. M.,
    8. Jenkins N. A.,
    9. Parada L. F.,
    10. Copeland N. G.
    (1994) Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev 8, 1019–1029
    OpenUrlAbstract/FREE Full Text
    1. Brown C. B.,
    2. Boyer A. S.,
    3. Runyan R. B.,
    4. Barnett J. V.
    (1996) Antibodies to the Type II TGFbeta receptor block cell activation and migration during atrioventricular cushion transformation in the heart. Dev. Biol 174, 248–257
    OpenUrlCrossRefPubMedWeb of Science
    1. Conway S.,
    2. Henderson D.,
    3. Copp A.
    (1997) Pax3 is required for cardiac neural crest migration in the mouse: evidence from the splotch (Sp2H) mutant. Development 124, 505–514
    OpenUrlAbstract
    1. Daston M. M.,
    2. Ratner N.
    (1992) Neurofibromin, a predominantly neuronal GTPase activating protein in the adult, is ubiquitously expressed during development. Dev. Dynam 195, 216–226
    OpenUrlCrossRefPubMedWeb of Science
    1. Eisenberg L. M.,
    2. Markwald R. R.
    (1995) Molecular regulation of atrioventricular valvuloseptal morphogenesis. Circulation Res 77, 1–6
    OpenUrlFREE Full Text
    1. Grinspan J. B.,
    2. Marchionni M. A.,
    3. Reeves M.,
    4. Coulaloglou M.,
    5. Scherer S. S.
    (1996) Axonal interactions regulate Schwann cell apoptosis in developing peripheral nerve: neuregulin receptors and the role of neuregulins. J. Neurosc 16, 6107–6118
    OpenUrlAbstract/FREE Full Text
    1. Guha A.,
    2. Lau N.,
    3. Huvar I.,
    4. Gutmann D.,
    5. Provias J.,
    6. Pawson T.,
    7. Boss G.
    (1996) Ras-GTP levels are elevated in human NF1 peripheral nerve tumors. Oncogene 12, 507–513
    OpenUrlPubMedWeb of Science
    1. Guo H. F.,
    2. The I.,
    3. Hannan F.,
    4. Bernards A.,
    5. Zhong Y.
    (1997) Requirement of Drosophila NF1 for activation of adenylyl cyclase by PACAP38-like neuropeptides. Science 276, 795–798
    OpenUrlAbstract/FREE Full Text
    1. Gutmann D. H.,
    2. Aylsworth A.,
    3. Carey J. C.,
    4. Korf B.,
    5. Marks J.,
    6. Pyeritz R. E.,
    7. Rubenstein A.,
    8. Viskochil D.
    (1997) The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. J. Am. Med Assoc 278, 51–57
    OpenUrlCrossRefPubMedWeb of Science
    1. Gutmann D. H.,
    2. Collins F. S.
    (1993) The neurofibromatosis type I gene and its protein product, neurofibromin. Neuron 10, 335–343
    OpenUrlCrossRefPubMedWeb of Science
    1. Hidai C.,
    2. Zupancic T.,
    3. Penta K.,
    4. Mikhail A.,
    5. Kawana M.,
    6. Quertermous E. E.,
    7. Aoka Y.,
    8. fukagawa M.,
    9. Matsui Y.,
    10. Platika D.,
    11. Auerbach R.,
    12. Hogan B. L. M.,
    13. Snodgrass R.,
    14. Quertermous T.
    (1998) Cloning and characterization of developmental endothelial locus-1: An embryonic endothelial cell protein that binds thev 3 integrin receptor. Genes Dev 12, 21–33
    OpenUrlAbstract/FREE Full Text
    1. Huynh D. P.,
    2. Nechiporuk T.,
    3. Pulst S. M.
    (1994) Differential expression and tissue distribution of type I and type II neurofibromins during mouse fetal development. Dev. Biol 161, 538–551
    OpenUrlCrossRefPubMedWeb of Science
    1. Jacks T.,
    2. Shih T. S.,
    3. Schmitt E. M.,
    4. Bronson R. T.,
    5. Bernards A.,
    6. Weinberg R. A.
    (1994) Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat. Genet 7, 353–361
    OpenUrlCrossRefPubMedWeb of Science
    1. Kim H. A.,
    2. Ling B.,
    3. Ratner N.
    (1997) Nf1-deficient mouse Schwann cells are angiogenic and invasive and can be induced to hyperproliferate: reversion of some phenotypes by an inhibitor of farnesyl protein transferase. Mol. Cell. Biol 17, 862–872
    OpenUrlAbstract/FREE Full Text
    1. Kim H. A.,
    2. Rosenbaum T.,
    3. Marchionni M. A.,
    4. Ratner N.,
    5. DeClue J. E.
    (1995) Schwann cells from neurofibromin deficient mice exhibit activation of p21ras, inhibition of cell proliferation and morphological changes. Oncogene 11, 325–335
    OpenUrlPubMedWeb of Science
    1. Kirby M. L.,
    2. Gale T. F.,
    3. Stewart D. E.
    (1983) Neural crest cells contribute to aorticopulmonary septation. Science 220, 1059–1061
    OpenUrlAbstract/FREE Full Text
    1. Kolodziejczyk S. M.,
    2. Hall B. K.
    (1996) Signal transduction and TGF-beta superfamily receptors. Biochem. Cell Biol 74, 299–314
    OpenUrlCrossRefPubMed
    1. Lamers W. H.,
    2. Viragh S.,
    3. Wessels A.,
    4. Moorman A. R. M.,
    5. Anderson R. H.
    (1995) Formation of the tricuspid valve in the human heart. Circulation 91, 111–121
    OpenUrlAbstract/FREE Full Text
    1. Largaespada D. A.,
    2. Brannan C. I.,
    3. Jenkins N. A.,
    4. Copeland N. G.
    (1996) Nf1 deficiency causes Ras-mediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukaemia. Nature Genet 12, 137–143
    OpenUrlCrossRefPubMedWeb of Science
    1. Leone G.,
    2. DeGregori J.,
    3. Sears R.,
    4. Jakoi L.,
    5. Nevins J. R.
    (1997) Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F. Nature 387, 422–426
    OpenUrlCrossRefPubMed
    1. Lutz B.,
    2. Kuratani S.,
    3. Cooney A.,
    4. Wawersik S.,
    5. Tsai S. Y.,
    6. Eichele G.,
    7. Tsai M.
    (1994) Developmental regulation of the orphan receptor COUP-TFII gene in spinal motor neurons. Development 120, 25–36
    OpenUrlAbstract
    1. Martin G. A.,
    2. Viskochil D.,
    3. Bollag G.,
    4. McCabe P. C.,
    5. Crosier W. J.,
    6. Haubruck H.,
    7. Conroy L.,
    8. Clark R.,
    9. O'Connell P.,
    10. Cawthon R. M.,
    11. Innis M. A.,
    12. McCormick F.
    (1990) The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 63, 843–849
    OpenUrlCrossRefPubMedWeb of Science
    1. Meyer D.,
    2. Birchmeier C.
    (1995) Multiple essential functions of neuregulin in development. Nature 378, 386–390
    OpenUrlCrossRefPubMedWeb of Science
    1. Nakajima Y.,
    2. Miyazono K.,
    3. Kato M.,
    4. Takase M.,
    5. Yamagishi T.,
    6. Nakamura H.
    (1997) Extracellular fibrillar structure of latent TGFbinding protein-1: Role in TGF -dependent endothelial-mesenchymal transformation during endocardial cushion tissue formation in mouse embryonic heart. J. Cell Biol 136, 193–204
    OpenUrlAbstract/FREE Full Text
    1. Potts J.,
    2. Runyan R.
    (1989) Epithelial-mesenchymal cell transformation in the embryonic heart can be mediated, in part, by tranformaing growth factor. Dev. Biol 134, 392–401
    OpenUrlCrossRefPubMedWeb of Science
    1. Ramsdell A. F.,
    2. Markwald R. R.
    (1997) Induction of endocardial cushion tissue in the avian heart is regulated, in part, by TGFbeta-3-mediated autocrine signaling. Dev. Biol 188, 64–74
    OpenUrlCrossRefPubMedWeb of Science
    1. Rosenbaum C.,
    2. Karyala S.,
    3. Marchionni M. A.,
    4. Kim H. A.,
    5. Krasnoselsky A. L.,
    6. Happel B.,
    7. Isaacs I.,
    8. Brackenbury R.,
    9. Ratner N.
    (1997) Schwann cells express NDF and SMDF/n-ARIA mRNAs, secrete neuregulin and show constitutive activation of erbB3 receptors: evidence for a neuregulin autocrine loop. Exp. Neurol 148, 604–615
    OpenUrlCrossRefPubMedWeb of Science
    1. Runyan R.,
    2. Markwald R.
    (1983) Invasion of mesenchyme into three-dimensional collagen gels: a regional and temporal analysis of interaction in embryonic heart tissue. Dev. Biol 95, 108–114
    OpenUrlCrossRefPubMedWeb of Science
    1. Runyan R. B.,
    2. Potts J. D.,
    3. Sharma R. V.,
    4. Loeber C. P.,
    5. Chiang J. J.,
    6. Bhalla R. C.
    (1990) Signal transduction of a tissue interaction during embryonic heart development. Cell Regulation 1, 301–313
    OpenUrlPubMedWeb of Science
    1. Sawada S.,
    2. Florell S.,
    3. Purandare S. M.,
    4. Ota M.,
    5. Stephens K.,
    6. Viskochil D.
    (1996) Identification of NF1 mutations in both alleles of a dermal neurofibroma. Nature Genet 14, 110–112
    OpenUrlCrossRefPubMedWeb of Science
    1. Schatteman G.,
    2. Motley S.,
    3. Effman E.,
    4. Bowen-Pope D.
    (1995) Platelet-derived growth factor receptor alpha subunit deleted Patch mouseexhibits severe cardiovascular dysmorphogenesis. Teratology 51, 351–366
    OpenUrlCrossRefPubMedWeb of Science
    1. Serra E.,
    2. Puig S.,
    3. Otero D.,
    4. Gaona A.,
    5. Kruyer H.,
    6. Ars E.,
    7. Estivill X.,
    8. Lazaro C.
    (1997) Confirmation of a double-hit model for the NF1 gene in benign neurofibromas. Am. J. Hum. Genet 61, 512–519
    OpenUrlCrossRefPubMedWeb of Science
    1. Side L.,
    2. Taylor B.,
    3. Cayouette M.,
    4. Conner E.,
    5. Thompson P.,
    6. Luce M.,
    7. Shannon K.
    (1997) Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders. New Engl. J. Med 336, 1713–1720
    OpenUrlCrossRefPubMedWeb of Science
    1. Sonnenberg E.,
    2. Meyer D.,
    3. Weidner K. M.,
    4. Birchmeier C.
    (1993) Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development. J. Cell Biol 123, 223–235
    OpenUrlAbstract/FREE Full Text
    1. Soriano P.
    (1997) The PDGF alpha receptor is required for neural crest cell development and for normal patterning of the somites. Development 124, 2691–2700
    OpenUrlAbstract
    1. Syroid D. E.,
    2. Maycox P. R.,
    3. Burrola P. G.,
    4. Liu N.,
    5. Wen D.,
    6. Lee K. F.,
    7. Lemke G.,
    8. Kilpatrick T. J.
    (1996) Cell death in the Schwann cell lineage and its regulation by neuregulin. Proc. Natl. Acad Sci. USA 93, 9229–9234
    OpenUrlAbstract/FREE Full Text
    1. Tassabehji M.,
    2. Strachan T.,
    3. Sharland M.,
    4. Colley A.,
    5. Donnai D.,
    6. Harris R.,
    7. Thakker N.
    (1993) Tandem duplication within a neurofibromatosis type 1 (NF1) gene exon in a family with features of Watson syndrome and Noonan syndrome. Am. J. Hum. Genet 53, 90–95
    OpenUrlPubMed
    1. The I.,
    2. Hannigan G. E.,
    3. Cowley G. S.,
    4. Reginald S.,
    5. Zhong Y.,
    6. Gusella J. F.,
    7. Hariharan I. K.,
    8. Bernards A.
    (1997) Rescue of a DrosophilaNF1 mutant phenotype by protein kinase A. Science 276, 791–794
    OpenUrlAbstract/FREE Full Text
    1. Xu G.,
    2. O'Connell P.,
    3. Viskochil D.,
    4. Cawthon R.,
    5. Robertson M.,
    6. Culver M.,
    7. Dunn D.,
    8. Stevens J.,
    9. Gesteland R.,
    10. White R.,
    11. Weiss R.
    (1990) The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62, 599–608
    OpenUrlCrossRefPubMedWeb of Science
    1. Yamamura H.,
    2. Zhang M.,
    3. Markwald R. R.,
    4. Mjaatvedt C. H.
    (1997) A heart segmental defect in the anterior-posterior axis of a transgenic mutant mouse. Dev. Biol 186, 58–72
    OpenUrlCrossRefPubMedWeb of Science
Back to top

 Download PDF

Email
JOURNAL ARTICLES
Neurofibromin modulation of ras activity is required for normal endocardial-mesenchymal transformation in the developing heart
M.M. Lakkis, J.A. Epstein
Development 1998 125: 4359-4367;
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Alerts

Article navigation

Other journals from The Company of Biologists

Advertisement

Kathryn Virginia Anderson (1952-2020)

Developmental geneticist Kathryn Anderson passed away at home on 30 November 2020. Tamara Caspary, a former postdoc and friend, remembers Kathryn and her remarkable contribution to developmental biology.

Zooming into 2021

In a new Editorial, Editor-in-Chief James Briscoe and Executive Editor Katherine Brown reflect on the triumphs and tribulations of the last 12 months, and look towards a hopefully calmer and more predictable year.

Read & Publish participation extends worldwide

Over 60 institutions in 12 countries are now participating in our Read & Publish initiative. Here, James Briscoe explains what this means for his institution, The Francis Crick Institute. Find out more and view our full list of participating institutions.

Upcoming special issues

Imaging Development, Stem Cells and Regeneration
Submission deadline: 30 March 2021
Publication: mid-2021

The Immune System in Development and Regeneration
Guest editors: Florent Ginhoux and Paul Martin
Submission deadline: 1 September 2021
Publication: Spring 2022

Both special issues welcome Review articles as well as Research articles, and will be widely promoted online and at key global conferences.

Development presents...

Our successful webinar series continues into 2021, with early-career researchers presenting their papers and a chance to virtually network with the developmental biology community afterwards. Sign up to join our next session:

10 February
Time: 13:00 (GMT)
Chaired by: preLights