The lymphatic system is crucial for the maintainance of good health and for the prevention and cure of disease. Congenital hypoplasia and failed regeneration of lymphatic tissue result in lymphedema. Primary lymphedema appears at birth (Milroy disease) or, more commonly, after puberty (Meige disease). Although lymphedema was first described more than a century ago, little progress has been made in understanding the mechanisms that cause it. Furthermore, little progress has been made in identifying the players that participate in the normal development of the lymphatic vasculature. Investigation of the normal development of the lymphatic system has been hindered by the lack of known lymphatic-specific markers. Consequently, hypotheses about the origin of the lymphatic vessels are still controversial. The most widely accepted view, which was proposed by F. Sabin in 1902, is that isolated primitive lymph sacs bud from the endothelium of veins during early development; from these primary lymph sacs, the peripheral lymphatic system spreads by endothelial sprouting into tissues where local capillaries form. This grant proposal is based in our identification of the homeobox gene Proxl as the first specific marker of lymphatic endothelial cells. Functional inactivation of Proxl in mice leads to phenotypic alterations in lymphatic vasculature and, ultimately, to embryo death. Detailed analyses of Proxl-null and Proxl heterozygous mice have indicated that lymphangiogenesis requires activity of Proxl in a subpopulation of endothelial cells in embryonic veins. Proxl-null mice are devoid of lymphatic vasculature. Proxl activity also determines the final lymphatic fate of budding endothelial cells. The elucidation of the molecular mechanisms by which Proxl participates in the formation of the lymphatic vasculature and the identification of other novel molecules that participates in this process will increase our understanding of normal lymphangiogenesis, and therefore, advance the treatment and prevention of disorders of the lymphatic system.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073402-04
Application #
7049442
Study Section
Pathology A Study Section (PTHA)
Program Officer
Goldman, Stephen
Project Start
2003-05-01
Project End
2007-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$366,188
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Louveau, Antoine; Herz, Jasmin; Alme, Maria Nordheim et al. (2018) CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat Neurosci 21:1380-1391
Louveau, Antoine; Filiano, Anthony J; Kipnis, Jonathan (2018) Meningeal whole mount preparation and characterization of neural cells by flow cytometry. Curr Protoc Immunol 121:
Gil, Hyea Jin; Ma, Wanshu; Oliver, Guillermo (2018) A novel podoplanin-GFPCre mouse strain for gene deletion in lymphatic endothelial cells. Genesis 56:e23102
Liu, Xiaolei; Gu, Xiaowu; Ma, Wanshu et al. (2018) Rasip1 controls lymphatic vessel lumen maintenance by regulating endothelial cell junctions. Development 145:
Ma, Wanshu; Oliver, Guillermo (2017) Lymphatic Endothelial Cell Plasticity in Development and Disease. Physiology (Bethesda) 32:444-452
Escobedo, Noelia; Oliver, Guillermo (2017) The Lymphatic Vasculature: Its Role in Adipose Metabolism and Obesity. Cell Metab 26:598-609
Escobedo, Noelia; Proulx, Steven T; Karaman, Sinem et al. (2016) Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice. JCI Insight 1:
Yang, Ying; Oliver, Guillermo (2014) Development of the mammalian lymphatic vasculature. J Clin Invest 124:888-97
Yang, Ying; Oliver, Guillermo (2014) Transcriptional control of lymphatic endothelial cell type specification. Adv Anat Embryol Cell Biol 214:5-22
Srinivasan, R Sathish; Escobedo, Noelia; Yang, Ying et al. (2014) The Prox1-Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors. Genes Dev 28:2175-87

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