GATA2 controls lymphatic endothelial cell junctional integrity and lymphovenous valve morphogenesis through <i>miR-126</i>

Mahamud, Md. Riaj; Geng, Xin; Ho, Yen Chun; Cha, Boksik; Kim, Yuenhee; Ma, Jing; Chen, Lijuan; Myers, Greggory; Camper, Sally A.; Mustacich, Debbie J.; Witte, Marlys H.; Choi, Dongwon; Hong, Young Kwon; Chen, Hong; Varshney, Gaurav K.; Engel, James Douglas; Wang, Shusheng; Kim, Tae Hoon; Lim, Kim Chew; Srinivasan, Ramesh

doi:10.1242/dev.184218

Cited by 34 publications

(32 citation statements)

References 71 publications

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“…PROX1, FOXC2, GATA2 and VEGFR3 are expressed at much higher levels in valvular endothelial cells compared to the rest of the lymphatic vasculature (Bazigou et al, 2009;Geng et al, 2016;Kazenwadel et al, 2015;Norrmen et al, 2009). Previous reports, including our own, have shown that PROX1, FOXC2 and GATA2 are necessary for the development of LVs and LVVs (Geng et al, 2016;Kazenwadel et al, 2015;Mahamud et al, 2019;Norrmen et al, 2009;Petrova et al, 2004). However, whether VEGFR3 is necessary for the development of valves has not been demonstrated although superficial venous valve reflex is observed in patients with Milroy's disease, which is characterized by heterozygous inactivating mutations in VEGFR3 (Mellor et al, 2010).…”

Section: Development • Accepted Manuscriptmentioning

confidence: 66%

YAP and TAZ maintain PROX1 expression in the developing lymphatic and lymphovenous valves in response to VEGF-C signaling

Cha

Geng

et al. 2020

Development

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Lymphatic vasculature is an integral part of digestive, immune and circulatory systems. The homeobox transcription factor PROX1 is necessary for the development of lymphatic vessels, lymphatic valves (LVs) and lymphovenous valves (LVVs). We and others previously reported a feedback loop between PROX1 and Vascular Endothelial Growth Factor-C (VEGF-C) signaling. PROX1 promotes the expression of the VEGF-C receptor VEGFR3 in lymphatic endothelial cells (LECs). In turn, VEGF-C signaling maintains PROX1 expression in LECs. However, the mechanisms of PROX1/VEGF-C feedback loop remain poorly understood. Whether VEGF-C signaling is necessary for LV and LVV development is also unknown. Here, we report for the first time that VEGF-C signaling is necessary for valve morphogenesis. We have also discovered that the transcriptional co-activators YAP and TAZ are required to maintain PROX1 expression in LVs and LVVs in response to VEGF-C signaling. Deletion of Yap and Taz in the lymphatic vasculature of mouse embryos did not affect the formation of LVs or LVVs, but resulted in the degeneration of these structures. Our results have identified VEGF-C/YAP/TAZ as a critical molecular pathway in valve development.

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Section: Development • Accepted Manuscriptmentioning

confidence: 66%

YAP and TAZ maintain PROX1 expression in the developing lymphatic and lymphovenous valves in response to VEGF-C signaling

Cha

Geng

et al. 2020

Development

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“…On the other hand, excessive stabilization of endothelial cell junctions in mice due to covalent fusion between VE-cadherin and α-catenin strongly suppresses embryonic lymphangiogenesis (Dartsch et al, 2014), suggesting that lymphatic development critically depends on the balanced adhesive strength of zipper junctions. PROX1 (Johnson et al, 2008), RASIP1 (Liu et al, 2018), GATA2 (Mahamud et al, 2019) and miR-126 (Mahamud et al, 2019) have been identified as important regulators of VE-cadherin as well as other junction proteins in developing lymphatics. In conclusion, several lines of evidence support that VE-cadherin dynamics at adherens junctions of zippers are very important for lymphatic vessel development (Baluk et al, 2007;Yang et al, 2012Yang et al, , 2019Yao et al, 2012;Hagerling et al, 2018).…”

Section: Lec Junctions In Developmentmentioning

confidence: 99%

Lymphatic Endothelial Cell Junctions: Molecular Regulation in Physiology and Diseases

Zhang

Zarkada

et al. 2020

Front. Physiol.

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Lymphatic endothelial cells (LECs) lining lymphatic vessels develop specialized cell-cell junctions that are crucial for the maintenance of vessel integrity and proper lymphatic vascular functions. Successful lymphatic drainage requires a division of labor between lymphatic capillaries that take up lymph via open "button-like" junctions, and collectors that transport lymph to veins, which have tight "zipper-like" junctions that prevent lymph leakage. In recent years, progress has been made in the understanding of these specialized junctions, as a result of the application of state-of-the-art imaging tools and novel transgenic animal models. In this review, we discuss lymphatic development and mechanisms governing junction remodeling between button and zipper-like states in LECs. Understanding lymphatic junction remodeling is important in order to unravel lymphatic drainage regulation in obesity and inflammatory diseases and may pave the way towards future novel therapeutic interventions.

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“…Da GATA2 eine essenzielle Rolle bei der Transkription einer Vielzahl von Genen, die an der Gefäßklappenmorphogenese beteiligt sind, spielt und somit bedeutend für die Morphogenese und Funktion der Lymphgefäßklappen ist [4,[7][8][9]14], sollten die Lymphgefäßklappen im Anschluss genauer untersucht werden.…”

Section: Resultateunclassified

“…Ferner kann durch das Fehlen der Gefäßklappen auf veränderte Flusseigenschaften in den Lymphgefäßen geschlossen werden, welches wiederum die Expression einer Vielzahl an Genen und hierdurch die Reifung der Gefäße beeinflusst [7][8][9].…”

Section: Diskussionunclassified

“…Obwohl die genetische Ursache bekannt ist und Tiermodelle die Bedeutung des Zinkfinger-Transkriptionsfaktors GATA2 für die Entstehung und Funktion der Lymphgefäße und lymphatischen Gefäßklappen zeigen konnten, ist die durch die Mutation hervorgerufene Veränderung auf das Lymphgefäßsystem im Menschen nicht abschließend geklärt [3,[7][8][9]. Ebenso ist unklar, warum im Rahmen des ES regelhaft nur die untere Extremität betroffen ist, die obere Extremität in der Regel jedoch keine Zeichen eines Lymphödems aufweist [3,10,11].…”

Section: Introductionunclassified

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Light sheet microscopy-based 3-dimensional histopathology of the lymphatic vasculature in Emberger syndrome

Hägerling

2020

Phlebologie

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Introduction Lymphovascular diseases represent a heterogenous group of inherited and sporadic disorders and refer to a range of possible underlying pathologies and pathogenesis.Emberger Syndrome, an inherited form of lymphedema, is characterized by bilateral lower limb lymphedema, however, upper limbs do not show any signs of swelling.To identify disease-associated histopathological alterations in patients with Emberger Syndrome and to elucidate potential histological differences between the lymphatic vasculature of upper and lower limbs, a detailed knowledge on the 3-dimensional tissue and vessel architecture is essential. However, the current gold standard in 2-dimensional histology provides only very limited spatial information. Material and methods To elucidate the underlying vascular pathology in Emberger Syndrome on the cellular level, we applied the 3-dimensional visualization and analysis approach VIPAR (volume information-based histopathological analysis by 3D reconstruction and data extraction) to entire wholemount immunofluorescence-stained human tissue samples. VIPAR is a light sheet microscopy-based imaging technique, which allows 3-dimensional reconstruction of entire tissue biopsies followed by automated and semi-automated analysis of vascular parameters in 3-dimensional space. Results Using VIPAR we could show that in Emberger Syndrome the dermal lymphatic vasculature is intact and non-disrupted.However, lower limbs showed an hypoplastic lymphatic vasculature with absence of lymphatic valves in pre-collecting and collecting vessels. In contrast to the lower limbs, the lymphatic vasculature of the upper limbs showed no morphological alterations of lymphatic vessels and lymphatic valves compared to healthy controls. Discussion Based on the 3-dimensional histopathological analysis we were able to perform a detailed phenotyping of lymphatic vessels in the upper and lower limb in Emberger Syndrome and to identify the underlying vascular pathology. In addition, we could show vascular alteration between the upper and lower limbs indicating a vascular heterogeneity of dermal lymph vessels causing the lower limb lymphedema.

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GATA2 controls lymphatic endothelial cell junctional integrity and lymphovenous valve morphogenesis through miR-126

Cited by 34 publications

References 71 publications

YAP and TAZ maintain PROX1 expression in the developing lymphatic and lymphovenous valves in response to VEGF-C signaling

YAP and TAZ maintain PROX1 expression in the developing lymphatic and lymphovenous valves in response to VEGF-C signaling

Lymphatic Endothelial Cell Junctions: Molecular Regulation in Physiology and Diseases

Light sheet microscopy-based 3-dimensional histopathology of the lymphatic vasculature in Emberger syndrome

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