T1 /podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema

Abstract

V.Schacht and M.I.Ramirez contributed equally to this workWithin the vascular system, the mucin-type transmembrane glycoprotein T1a/podoplanin is predominantly expressed by lymphatic endothelium, and recent studies have shown that it is regulated by the lymphatic-speci®c homeobox gene Prox1. In this study, we examined the role of T1a/podoplanin in vascular development and the effects of gene disruption in mice. T1a/podoplanin is ®rst 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. T1a/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. T1a/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 T1a/podoplanin promotes cell adhesion, migration and tube formation, whereas small interfering RNA-mediated inhibition of T1a/podoplanin expression decreased lymphatic endothelial cell adhesion. These data identify T1a/podoplanin as a novel critical player that regulates different key aspects of lymphatic vasculature formation.

Low podoplanin expression in pretreatment biopsy material predicts poor prognosis in advanced-stage squamous cell carcinoma of the uterine cervix treated by primary radiation

“…It was recently reported that mice deficient in podoplanin develop congenital lymphedema and have defects in lymphatic vessel, but not blood vessel, formation. 23 In vitro studies suggested that podoplanin may be involved in mediating cell motility and adhesion. 23,24 Very recently, podoplanin expression was reported in squamous cell carcinomas of the epidermis, 13 oral cavity, 24 and lung, 25 and it was suggested that it may be involved in tumor cell invasion, metastasis, and tumor progression.…”

The potential role of podoplanin in tumour invasion

“…Podoplanin-deficient mice die at birth owing to respiratory failure exhibiting a phenotype of dilated, malfunctioning lymphatic vessels and lymphoedema Schacht et al, 2003). In addition, podoplanin can induce platelet aggregation in vitro .…”

Development of the lymphatic vascular system: A mystery unravels

“…Podoplanin is a mucin-type transmembrane glycoprotein that is expressed by lymphatic, but not by blood vascular endothelial cells in vivo and in vitro (Wetterwald et al, 1996;Kriehuber et al, 2001;Petrova et al, 2002;Hirakawa et al, 2003;Schacht et al, 2003). In addition, podoplanin is expressed by several other cell types, including type I alveolar cells of the lung, cells of the choroid plexus, ciliary epithelial cells of the eye, osteocytes and kidney podocytes, and multiple synonyms have been used in the literature, such as RTI40, murine gp38, canine gp40, human gp36, and murine PA2.26 Schacht et al, 2003).…”

“…In addition, podoplanin is expressed by several other cell types, including type I alveolar cells of the lung, cells of the choroid plexus, ciliary epithelial cells of the eye, osteocytes and kidney podocytes, and multiple synonyms have been used in the literature, such as RTI40, murine gp38, canine gp40, human gp36, and murine PA2.26 Schacht et al, 2003). During mouse embryonic development, podoplanin is expressed at around E9 in the central nervous system and the foregut but not yet in the vascular system (Rishi et al, 1995;Ramirez et al, 2003;Schacht et al, 2003). At E11.5-E12.5, podoplanin is expressed by all endothelial cells in the cardinal vein, including the budding Prox1-positive cells .…”

“…At birth, the expression of podoplanin is restricted to lymphatic endothelial cells, whereas ectopic expression of Prox1 up-regulated podoplanin in adult blood vascular endothelial cells (Hong et al, 2002). Podoplanin-deficient mice die at birth due to lung failure Schacht et al, 2003). Importantly, neonatal mutant mice display cutaneous lymphedema associated with impaired lymphatic transport .…”