Connexin37 and Connexin43 deficiencies in mice disrupt lymphatic valve development and result in lymphatic disorders including lymphedema and chylothorax.

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  • Author(s): Kanady JD;Kanady JD; Dellinger MT; Munger SJ; Witte MH; Simon AM
  • Source:
    Developmental biology [Dev Biol] 2011 Jun 15; Vol. 354 (2), pp. 253-66. Date of Electronic Publication: 2011 Apr 16.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: United States NLM ID: 0372762 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-564X (Electronic) Linking ISSN: 00121606 NLM ISO Abbreviation: Dev Biol Subsets: MEDLINE
    • Publication Information:
      Publication: San Diego, CA : Elsevier
      Original Publication: New York.
    • Subject Terms:
      Lymphangiogenesis*; Chylothorax/*genetics ; Connexin 43/*metabolism ; Connexins/*metabolism ; Lymphatic Vessels/*abnormalities ; Lymphedema/*genetics; Animals ; Chylothorax/pathology ; Chylothorax/physiopathology ; Connexin 43/genetics ; Connexins/genetics ; Forkhead Transcription Factors/metabolism ; Lymphatic Vessels/metabolism ; Lymphedema/pathology ; Lymphedema/physiopathology ; Mice ; Mice, Knockout ; Gap Junction alpha-4 Protein
    • Abstract:
      Intraluminal valves are required for the proper function of lymphatic collecting vessels and large lymphatic trunks like the thoracic duct. Despite recent progress in the study of lymphvasculogenesis and lymphangiogenesis, the molecular mechanisms controlling the morphogenesis of lymphatic valves remain poorly understood. Here, we report that gap junction proteins, or connexins (Cxs), are required for lymphatic valvulogenesis. Cx37 and Cx43 are expressed early in mouse lymphatic development in the jugular lymph sacs, and later in development these Cxs become enriched and differentially expressed by lymphatic endothelial cells on the upstream and downstream sides of the valves. Specific deficiencies of Cx37 and Cx43 alone or in combination result in defective valve formation in lymphatic collecting vessels, lymphedema, and chylothorax. We also show that Cx37 regulates jugular lymph sac size and that both Cx37 and Cx43 are required for normal thoracic duct development, including valve formation. Another Cx family member, Cx47, whose human analog is mutated in some families with lymphedema, is also highly enriched in a subset of endothelial cells in lymphatic valves. Mechanistically, we present data from Foxc2-/- embryos suggesting that Cx37 may be a target of regulation by Foxc2, a transcription factor that is mutated in human lymphedema-distichiasis syndrome. These results show that at least three Cxs are expressed in the developing lymphatic vasculature and, when defective, are associated with clinically manifest lymphatic disorders in mice and man.
      (Copyright © 2011 Elsevier Inc. All rights reserved.)
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    • Grant Information:
      R01 HL064232 United States HL NHLBI NIH HHS; R01 HL064232-09 United States HL NHLBI NIH HHS; T32 HL007249 United States HL NHLBI NIH HHS; HL64232 United States HL NHLBI NIH HHS
    • Accession Number:
      0 (Connexin 43)
      0 (Connexins)
      0 (Forkhead Transcription Factors)
      0 (GJA1 protein, mouse)
      0 (connexin 47)
      0 (mesenchyme fork head 1 protein)
    • Publication Date:
      Date Created: 20110426 Date Completed: 20110804 Latest Revision: 20231213
    • Publication Date:
      20231215
    • Accession Number:
      PMC3134316
    • Accession Number:
      10.1016/j.ydbio.2011.04.004
    • Accession Number:
      21515254