The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of <i>Prox1</i> expression in lymphatic endothelial cells

Srinivasan, Ramesh; Geng, Xin; Yang, Ying; Wang, Yingdi; Mukatira, Suraj; Studer, Michèle; Porto, Marianna Picarelli Ribeiro; Lagutin, Oleg V.; Oliver, Guillermo

doi:10.1101/gad.1859310

Cited by 250 publications

(271 citation statements)

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“…COUP-TFII deletion resulted in abnormal arterialization of the veins by misexpression of the Notch pathway genes in the venous compartment, whereas ectopic COUP-TFII overexpression in vivo induced the excessive venous endothelial phenotype at the expense of arterial endothelial cells (You et al 2005). Importantly, COUP-TFII has been identified as an interacting partner of Prox1 in vitro and in vivo, and the functional interaction between the two cellfate regulators was proposed to constitute an essential part in the program specifying LEC fate Yamazaki et al 2009;Srinivasan et al 2010). Supporting this notion, conditional ablation of COUP-TFII at an early embryonic stage blocked the LEC-fate specification of the venous endothelial cells and formation of lymphatic vessels (Lin et al 2010).…”

Section: Initial Steps For Lymphatic Specification and Differentiationmentioning

confidence: 99%

“…Notch, which is selectively expressed in arterial endothelial cells and acts as a downstream effector of VEGF-induced arterialization signal (Lawson et al 2001Weinstein and Lawson 2002;Lanner et al 2007;Siekmann and Lawson 2007), represses the expression of COUP-TFII, Prox1, and podoplanin through Hey1 . COUP-TFII, a nuclear receptor that is selectively expressed in the venous compartment, has been shown to interact physically and functionally with Prox1 in LECs to direct a developmental program that specifies LEC fate Yamazaki et al 2009;Kang et al 2010;Srinivasan et al 2010). Interestingly, Prox1 and COUP-TFII concertedly suppress VEGF signaling by downregulating the expression of the major VEGF receptors VEGFR-2 and NRP-1 .…”

Section: Plasticity Of Lymphatic Endothelial Cell Fate-lymphatic Equimentioning

confidence: 99%

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The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

Choi

Lee²,

Hong

2012

Cold Spring Harbor Perspectives in Medicine

116

104

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The blood and lymphatic systems are the two major circulatory systems in our body. Although the blood system has been studied extensively, the lymphatic system has received much less scientific and medical attention because of its elusive morphology and mysterious pathophysiology. However, a series of landmark discoveries made in the past decade has begun to change the previous misconception of the lymphatic system to be secondary to the more essential blood vascular system. In this article, we review the current understanding of the development and pathology of the lymphatic system. We hope to convince readers that the lymphatic system is no less essential than the blood circulatory system for human health and well-being.

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Section: Initial Steps For Lymphatic Specification and Differentiationmentioning

confidence: 99%

Section: Plasticity Of Lymphatic Endothelial Cell Fate-lymphatic Equimentioning

confidence: 99%

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

Choi

Lee²,

Hong

2012

Cold Spring Harbor Perspectives in Medicine

116

104

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“…However, considering our finding that LEC progenitors are present not only in the CV but also in the ISVs, we decided to re-evaluate our original interpretation by examining thick sections of Prox1-null embryos in which the entire structure of the ISVs was retained. Immunostained transverse and sagittal vibratome sections (100 m) of E10.5 Prox1 GFPCre/GFPCre embryos (which display the same phenotype as the original Prox1 LacZ/LacZ embryos) 11 showed GFP ϩ cells (these cells represent cells in which the Prox1 promoter was activated, but no functional protein was produced) only in the CV and ISVs of these embryos ( Figure 6A-D arrowheads, n ϭ 3 embryos). Unlike in WT littermates or heterozygous littermates, null embryos had no GFP ϩ cells budding from the CV or ISVs (Figure 6A-D).…”

Section: Prox1 Is Essential For Lec Progenitors To Leave the CVmentioning

confidence: 99%

“…The methods for generating Prox1 ϩ/LacZ , COUP-TFII flox/flox , and Prox1 ϩ/GFPCre mice were previoulsy reported. 4,10,11 PlexinD1 Ϫ/Ϫ embryos were previously described. 12 All of the mouse experiments were approved by the St Jude Children's Research Hospital Animal Care and Use Committee.…”

Section: Micementioning

confidence: 99%

Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos

Yang

García‐Verdugo

Soriano-Navarro

et al. 2012

Blood

Self Cite

192

189

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The lymphatic vasculature preserves tissue fluid balance by absorbing fluid and macromolecules and transporting them to the blood vessels for circulation. The stepwise process leading to the formation of the mammalian lymphatic vasculature starts by the expression of the gene Prox1 in a subpopulation of blood endothelial cells (BECs) on the cardinal vein (CV) at approximately E9.5. These Prox1-expressing lymphatic endothelial cells (LECs) will exit the CV to form lymph sacs, primitive structures from which the entire lymphatic network is derived. Until now, no conclusive information was available regarding the cellular processes by which these LEC progenitors exit the CV without compromising the vein's integrity. We determined that LECs leave the CV by an active budding mechanism. During this process, LEC progenitors are interconnected by VE-cadherin-expressing junctions. Surprisingly, we also found that Prox1-expressing LEC progenitors were present not only in the CV but also in the intersomitic vessels (ISVs). Furthermore, as LEC progenitors bud from the CV and ISVs into the surrounding mesenchyme, they begin expressing the lymphatic marker podoplanin, migrate away from the CV, and form the lymph sacs. Analyzing this process in Prox1-null embryos revealed that Prox1 activity is necessary for LEC progenitors to exit the CV. (Blood. 2012;120(11):2340-2348) IntroductionOur understanding of the genes and mechanisms controlling the development of the mammalian lymphatic vasculature has greatly advanced in the last decade. The results of targeted inactivation experiments in mice have identified 3 transcription factors (Prox1, Sox18, and COUP-TFII) as crucial regulators of early lymphatic endothelial cell (LEC) differentiation in mammals; their functional inactivation results in a complete lack of LECs and, therefore, of the entire lymphatic vasculature. [1][2][3][4] It is generally accepted that the initiation of Prox1 expression in a subpopulation of venous endothelial cells (VECs) in the wall of the mouse cardinal vein (CV) at around E9.5 is one of the earliest steps during mammalian lymphatic vasculature formation. We have previously shown that the embryonic veins are the unique source of the entire mammalian lymphatic vasculature by showing that Prox1-expressing LECs that exit the CV form the embryonic lymph sacs from which the entire lymphatic vasculature is eventually derived. 2,5 Although it is known that in mammals Vegfc signaling is required for LECs to exit the CV, 6 until now no conclusive data were available regarding the cellular mechanisms involved in this critical process. For instance, how do these endothelial cells (ECs) exit the CV? How is it that LECs leave the CV without disrupting the endothelial barrier? To address some of these important questions, we performed electron microscopy (EM) to visualize Prox1-expressing LEC progenitors leaving the CV. Results from these analyses determined that Prox1-expressing LEC progenitors leave the CV by budding and that the integrity of the CV is not compromi...

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“…Prox1-eGFP/Cre is a knockin line where an eGFP/Cre fusion protein was inserted downstream of the Prox1 translation start site (Srinivasan et al 2010). This allele was recently characterized in the cochlea using the ROSA26 eYFP reporter line.…”

Section: Cre/creer Lines For the Developing Vestibular Organsmentioning

confidence: 99%

Conditional Gene Expression in the Mouse Inner Ear Using Cre-loxP

Cox

Liu

Lagarde

et al. 2012

JARO

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In recent years, there has been significant progress in the use of Cre-loxP technology for conditional gene expression in the inner ear. Here, we introduce the basic concepts of this powerful technology, emphasizing the differences between Cre and CreER. We describe the creation and Cre expression pattern of each Cre and CreER mouse line that has been reported to have expression in auditory and vestibular organs. We compare the Cre expression patterns between Atoh1-CreER TM and Atoh1-CreER T2 and report a new line, Fgfr3-iCreER T2 , which displays inducible Cre activity in cochlear supporting cells. We also explain how results can vary when transgenic vs. knock-in Cre/CreER alleles are used to alter gene expression. We discuss practical issues that arise when using the Cre-loxP system, such as the use of proper controls, Cre efficiency, reporter expression efficiency, and Cre leakiness. Finally, we introduce other methods for conditional gene expression, including Flp recombinase and the tetracycline-inducible system, which can be combined with Cre-loxP mouse models to investigate conditional expression of more than one gene.

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The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells

Cited by 250 publications

References 35 publications

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos

Conditional Gene Expression in the Mouse Inner Ear Using Cre-loxP

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