View the Current Issue

Article

  • The EMBO Journal (2003) 22, 3546 - 3556
  • doi:10.1093/emboj/cdg342

T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema

Vivien Schacht1,6, Maria I. Ramirez2,6, Young-Kwon Hong1, Satoshi Hirakawa1, Dian Feng3, Natasha Harvey4, Mary Williams2,5, Ann M. Dvorak3, Harold F. Dvorak3, Guillermo Oliver4 and Michael Detmar1

  1. Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
  2. Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
  3. Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
  4. Department of Genetics, St Jude Children's Hospital, Memphis, TN 38105, USA
  5. Department of Anatomy, Boston University School of Medicine, Boston, MA 02118, USA
  6. V.Schacht and M.I.Ramirez contributed equally to this work

Correspondence to:

Michael Detmar, E-mail: michael.detmar@cbrc2.mgh.harvard.edu

Received 20 January 2003; Accepted 19 May 2003; Revised 13 May 2003

Within the vascular system, the mucin-type transmembrane glycoprotein T1alpha/podoplanin is predominantly expressed by lymphatic endothelium, and recent studies have shown that it is regulated by the lymphatic-specific homeobox gene Prox1. In this study, we examined the role of T1alpha/podoplanin in vascular development and the effects of gene disruption in mice. T1alpha/podoplanin is first expressed at around E11.0 in Prox1-positive lymphatic progenitor cells, with predominant localization in the luminal plasma membrane of lymphatic endothelial cells during later development. T1alpha/podoplanin-/- mice die at birth due to respiratory failure and have defects in lymphatic, but not blood vessel pattern formation. These defects are associated with diminished lymphatic transport, congenital lymphedema and dilation of lymphatic vessels. T1alpha/podoplanin is also expressed in the basal epidermis of newborn wild-type mice, but gene disruption did not alter epidermal differentiation. Studies in cultured endothelial cells indicate that T1alpha/podoplanin promotes cell adhesion, migration and tube formation, whereas small interfering RNA-mediated inhibition of T1alpha/podoplanin expression decreased lymphatic endothelial cell adhesion. These data identify T1alpha/podoplanin as a novel critical player that regulates different key aspects of lymphatic vasculature formation.

  • Keywords:

    • angiogenesis,
    • lymphangiogenesis,
    • podoplanin,
    • Prox1,
    • T1alpha