FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1

The mechanisms of blood vessel maturation into distinct parts of the blood vasculature such as arteries, veins, and capillaries have been the subject of intense investigation over recent years. In contrast, our knowledge of lymphatic vessel maturation is still fragmentary. In this study, we provide a molecular and morphological characterization of the major steps in the maturation of the primary lymphatic capillary plexus into collecting lymphatic vessels during development and show that forkhead transcription factor Foxc2 controls this process. We further identify transcription factor NFATc1 as a novel regulator of lymphatic development and describe a previously unsuspected link between NFATc1 and Foxc2 in the regulation of lymphatic maturation. We also provide a genome-wide map of FOXC2-binding sites in lymphatic endothelial cells, identify a novel consensus FOXC2 sequence, and show that NFATc1 physically interacts with FOXC2-binding enhancers. As damage to collecting vessels is a major cause of lymphatic dysfunction in humans, our results suggest that FOXC2 and NFATc1 are potential targets for therapeutic intervention.

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Autoregulated Expression of Schizosaccharomyces pombe Meiosis-Specific Transcription Factor Mei4 and a Genome-Wide Search for Its Target Genes

Genetics ◽

10.1093/genetics/154.4.1497 ◽

2000 ◽

Vol 154 (4) ◽

pp. 1497-1508 ◽

Cited By ~ 4

Author(s):

Hiroko Abe ◽

Chikashi Shimoda

Keyword(s):

Transcription Factor ◽

Schizosaccharomyces Pombe ◽

Target Genes ◽

Northern Blotting ◽

Forkhead Transcription Factor ◽

Gene Encoding ◽

Putative Promoter Region ◽

Cis Acting ◽

A Genome ◽

Genome Wide Search

Abstract The Schizosaccharomyces pombe mei4+ gene encoding a forkhead transcription factor is necessary for the progression of meiosis and sporulation. We searched for novel meiotic genes, the expression of which is dependent on Mei4p, since only the spo6+ gene has been assigned to its targets. Six known genes responsible for meiotic recombination were examined by Northern blotting, but none were Mei4 dependent for transcription. We determined the important cis-acting element, designated FLEX, to which Mei4p can bind. The S. pombe genome sequence database (The Sanger Centre, UK) was scanned for the central core heptamer and its flanking 3′ sequence of FLEX composed of 17 nucleotides, and 10 candidate targets of Mei4 were selected. These contained a FLEX-like sequence in the 5′ upstream nontranslatable region within 1 kb of the initiation codon. Northern blotting confirmed that 9 of them, named mde1+ to mde9+, were transcriptionally induced during meiosis and were dependent on mei4+. Most mde genes have not been genetically defined yet, except for mde9+, which is identical to spn5+, which encodes one of the septin family of proteins. mde3+ and a related gene pit1+ encode proteins related to Saccharomyces cerevisiae Ime2. The double disruptant frequently produced asci having an abnormal number and size of spores, although it completed meiosis. We also found that the forkhead DNA-binding domain of Mei4p binds to the FLEX-like element in the putative promoter region of mei4 and that the maximum induction level of mei4 mRNA required functional mei4 activity. Furthermore, expression of a reporter gene driven by the authentic mei4 promoter was induced in vegetative cells by ectopic overproduction of Mei4p. These results suggest that mei4 transcription is positively autoregulated.

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Forkhead transcription factor FOXC2 regulates regeneration of lymphatic vessels

Vascular Pharmacology ◽

10.1016/j.vph.2011.08.156 ◽

2012 ◽

Vol 56 (5-6) ◽

pp. 363

Author(s):

Hélène Maby-El Hajjami ◽

Romain Legrand ◽

Naoyuki Miura ◽

Tatiana V. Petrova

Keyword(s):

Transcription Factor ◽

Lymphatic Vessels ◽

Forkhead Transcription Factor

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Faculty Opinions recommendation of Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.11326959.14375054 ◽

2011 ◽

Author(s):

Pankaj Kapahi

Keyword(s):

Transcription Factor ◽

Life Span ◽

Forkhead Transcription Factor ◽

C Elegans

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Mechanisms and cell lineages in lymphatic vascular development

Angiogenesis ◽

10.1007/s10456-021-09784-8 ◽

2021 ◽

Author(s):

Daniyal J. Jafree ◽

David A. Long ◽

Peter J. Scambler ◽

Christiana Ruhrberg

Keyword(s):

Emerging Technologies ◽

Vascular Development ◽

Lymphatic Vessels ◽

Experimental Techniques ◽

Knowledge Gaps ◽

Cellular Mechanisms ◽

Cell Lineages ◽

Lymphatic Vasculature ◽

Lymphatic Development ◽

Health And Disease

AbstractLymphatic vessels have critical roles in both health and disease and their study is a rapidly evolving area of vascular biology. The consensus on how the first lymphatic vessels arise in the developing embryo has recently shifted. Originally, they were thought to solely derive by sprouting from veins. Since then, several studies have uncovered novel cellular mechanisms and a diversity of contributing cell lineages in the formation of organ lymphatic vasculature. Here, we review the key mechanisms and cell lineages contributing to lymphatic development, discuss the advantages and limitations of experimental techniques used for their study and highlight remaining knowledge gaps that require urgent attention. Emerging technologies should accelerate our understanding of how lymphatic vessels develop normally and how they contribute to disease.

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The Notch1-Dll4 signaling pathway regulates mouse postnatal lymphatic development

Blood ◽

10.1182/blood-2010-11-319129 ◽

2011 ◽

Vol 118 (7) ◽

pp. 1989-1997 ◽

Cited By ~ 61

Author(s):

Kyle Niessen ◽

Gu Zhang ◽

John Brady Ridgway ◽

Hao Chen ◽

Ganesh Kolumam ◽

...

Keyword(s):

Blood Vessel ◽

Notch Signaling ◽

Signaling Pathway ◽

Lymphatic Vessels ◽

Mouse Skin ◽

Notch Signaling Pathway ◽

Cell Phenotype ◽

Mural Cell ◽

Lymphatic Development ◽

Vessel Development

Abstract The Notch signaling pathway plays a fundamental role during blood vessel development. Notch signaling regulates blood vessel morphogenesis by promoting arterial endothelial differentiation and pro-viding spatial and temporal control over “tip cell” phenotype during angiogenic sprouting. Components of the Notch signaling pathway have emerged as potential regulators of lymphatic development, joining the increasing examples of blood vessel regulators that are also involved in lymphatic development. However, in mammals a role for the Notch signaling pathway during lymphatic development remains to be demonstrated. In this report, we show that blockade of Notch1 and Dll4, with specific function-blocking antibodies, results in defective postnatal lymphatic development in mice. Mechanistically, Notch1-Dll4 blockade is associated with down-regulation of EphrinB2 expression, been shown to be critically involved in VEGFR3/VEGFC signaling, resulting in reduced lymphangiogenic sprouting. In addition, Notch1-Dll4 blockade leads to compromised expression of distinct lymphatic markers and to dilation of collecting lymphatic vessels with reduced and disorganized mural cell coverage. Finally, Dll4-blockade impairs wound closure and severely affects lymphangiogenesis during the wound healing in adult mouse skin. Thus, our study demonstrates for the first time in a mammalian system that Notch1-Dll4 signaling pathway regulates postnatal lymphatic development and pathologic lymphangiogenesis.

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