Role of LAT-1 in trophoblast migration and embryo implantation

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Role of LAT-1 in trophoblast migration and embryo implantation
Chrostowski, Magdalena K. (creator)
Padbury, James (director)
Thompsom, Nancy (reader)
Gruppuso, Philip (reader)
Wessel, Gary (reader)
Sutherland, Ann (reader)
Brown University. Division of Biology and Medicine. Pathobiology (sponsor)
Copyright Date
LAT1 is a Na+-independent amino acid transporter of system L. It is a member of the 12-membrane-spanning domain protein family. It is one of the major routes for growing cells to take up large neutral branched or aromatic amino acids. It requires association with another membrane spanning protein named 4F2hc for functional transport. The LAT1 and 4F2hc heterodimeric complex is formed via interactions of the 4F2hc extracellular domain and a disulfide bond. Although the expression of 4F2hc is ubiquitous, the expression of LAT1 is restricted; its highest expression is in brain, placenta and various tumors. Because of its high expression and its association with aggressive tumor invasion, it is a potential therapeutic target. Inhibition of LAT1 activity in tumor cells inhibits growth by depriving cells of essential amino acids. Since the placenta is highly proliferative and invasive tissue, it has been proposed to serve as a model to study tumor biology. We have evaluated this role of LAT1 in the placenta. We show that LAT1 is expressed in all stages of pre-implantation embryos and that its expression increases as the embryo develops form zygote to blastocyst. In the post-implantation stages of mouse embryo development the highest expression of LAT1 was found in invasive trophoblast giant cells (TGCs) at E7.5, suggesting its role in trophoblast migration and invasion. To test this, we carried out gain of function and loss of function studies in primary trophoblast stem (TS) cells. Deprivation of leucine in the culture media, as well as pharmacologic inhibition of system L transport led to increased LAT-1 expression and increased ability of these cells to invade the extracellular matrix. The gene silencing experiments with siRNA's targeting LAT1, led to downregulation of LAT1 expression and decreased migration/invasion. We conclude that LAT1 serves not only to transport essential amino acids necessary for cell growth and proliferation but also plays an important role in trophoblast invasion and placental formation.
Amino acid transport
Amino acids--Physiological transport
Thesis (Ph.D.) -- Brown University (2009)
xxiii, 178 p.


Chrostowski, Magdalena K., "Role of LAT-1 in trophoblast migration and embryo implantation" (2009). Biology and Medicine Theses and Dissertations, Pathobiology Theses and Dissertations. Brown Digital Repository. Brown University Library.