title: ADAM10-Dependent Signaling Through Notch1 and Notch4 Controls Development of Organ-Specific Vascular Beds.
abstract: BACKGROUND
  Endothelial Notch signaling is critical for early vascular development and survival. Yet, previously described mice lacking endothelial a disintegrin and metalloproteinase 10 (ADAM10), a key regulator of Notch signaling, survived into adulthood with organ-specific vascular defects. These findings raised questions about whether these vascular defects were related to Notch signaling or other functions of ADAM10.
  
  
  OBJECTIVE
  The aims of the study are to determine whether compensatory or redundant functions of ADAM17 in Notch signaling can explain the survival of Adam10ΔEC mice, explore the contribution of different Tie2-Cre transgenes to the differences in survival, and establish whether the Adam10ΔEC vascular phenotypes can be recapitulated by inactivation of Notch receptors in endothelial cells.
  
  
  RESULTS
  Mice lacking ADAM10 and ADAM17 in endothelial cells (Adam10/Adam17ΔEC), which survived postnatally with organ-specific vascular defects, resembled Adam10ΔEC mice. In contrast, Adam10ΔEC mice generated with the Tie2Cre transgene previously used to inactivate endothelial Notch (Adam10ΔEC(Flv)) died by E10.5. Quantitative polymerase chain reaction analysis demonstrated that Cre-mediated recombination occurs earlier in Adam10ΔEC(Flv) mice than in the previously described Adam10ΔEC mice. Finally, mice lacking endothelial Notch1 (Notch1ΔEC) share some organ-specific vascular defects with Adam10ΔEC mice, whereas Notch4(-/-) mice lacking endothelial Notch1 (Notch1ΔEC/Notch4(-/-)) had defects in all vascular beds affected in Adam10ΔEC mice.
  
  
  CONCLUSIONS
  Our results argue against a major role for ADAM17 in endothelial Notch signaling and clarify the difference in phenotypes of previously described mice lacking ADAM10 or Notch in endothelial cells. Most notably, these findings uncover new roles for Notch signaling in the development of organ-specific vascular beds.
authors.affiliation: From the Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY (R.O.A., K.G., C.H., G.W., C.P.B.); Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, NY (R.O.A., K.G., C.P.B.); Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medicine, Rockefeller University, New York, NY (S.M.); Institute for Advanced Study, Technical University Munich, Munich, Germany (C.P.B.); and Departments of Medicine and of Physiology, Systems Biology and Biophysics, Weill Cornell Medicine, New York, NY (C.P.B.).
authors.forename: Rolake O
authors.initials: RO
authors.lastname: Alabi
authors.affiliation: From the Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY (R.O.A., K.G., C.H., G.W., C.P.B.); Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, NY (R.O.A., K.G., C.P.B.); Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medicine, Rockefeller University, New York, NY (S.M.); Institute for Advanced Study, Technical University Munich, Munich, Germany (C.P.B.); and Departments of Medicine and of Physiology, Systems Biology and Biophysics, Weill Cornell Medicine, New York, NY (C.P.B.).
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Glomski
authors.affiliation: From the Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY (R.O.A., K.G., C.H., G.W., C.P.B.); Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, NY (R.O.A., K.G., C.P.B.); Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medicine, Rockefeller University, New York, NY (S.M.); Institute for Advanced Study, Technical University Munich, Munich, Germany (C.P.B.); and Departments of Medicine and of Physiology, Systems Biology and Biophysics, Weill Cornell Medicine, New York, NY (C.P.B.).
authors.forename: Coline
authors.initials: C
authors.lastname: Haxaire
authors.affiliation: From the Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY (R.O.A., K.G., C.H., G.W., C.P.B.); Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, NY (R.O.A., K.G., C.P.B.); Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medicine, Rockefeller University, New York, NY (S.M.); Institute for Advanced Study, Technical University Munich, Munich, Germany (C.P.B.); and Departments of Medicine and of Physiology, Systems Biology and Biophysics, Weill Cornell Medicine, New York, NY (C.P.B.).
authors.forename: Gisela
authors.initials: G
authors.lastname: Weskamp
authors.affiliation: From the Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY (R.O.A., K.G., C.H., G.W., C.P.B.); Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, NY (R.O.A., K.G., C.P.B.); Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medicine, Rockefeller University, New York, NY (S.M.); Institute for Advanced Study, Technical University Munich, Munich, Germany (C.P.B.); and Departments of Medicine and of Physiology, Systems Biology and Biophysics, Weill Cornell Medicine, New York, NY (C.P.B.).
authors.forename: Sébastien
authors.initials: S
authors.lastname: Monette
authors.affiliation: From the Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY (R.O.A., K.G., C.H., G.W., C.P.B.); Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, NY (R.O.A., K.G., C.P.B.); Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medicine, Rockefeller University, New York, NY (S.M.); Institute for Advanced Study, Technical University Munich, Munich, Germany (C.P.B.); and Departments of Medicine and of Physiology, Systems Biology and Biophysics, Weill Cornell Medicine, New York, NY (C.P.B.). blobelc@hss.edu.
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
mesh_terms: D000072197:ADAM10 Protein / Q000172:deficiency / Q000502:physiology*; D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D001775:Blood Circulation / Q000502:physiology*; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D008565:Membrane Proteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000502:physiology*; D051881:Receptor, Notch1 / Q000172:deficiency / Q000502:physiology*; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000172:deficiency / Q000502:physiology*; D012039:Regional Blood Flow / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D000074562:Receptor, Notch4; D051880:Receptors, Notch; C073572:Notch4 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse
keywords: bone development; disintegrins; embryonic development; endothelial cells; phenotype; transgenes