Cdk5 controls lymphatic vessel development and function by phosphorylation of Foxc2

Liebl, Johanna; Zhang, Siwei; Moser, Markus; Agalarov, Yan; Demir, Cansaran Saygili; Hager, Bianca; Bibb, James A.; Adams, Ralf H.; Kiefer, Friedemann; Miura, Naoyuki; Petrova, Tatiana V.; Vollmar, Angelika M.; Zahler, Stefan

doi:10.1038/ncomms8274

Cited by 41 publications

(43 citation statements)

References 45 publications

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“…In lymphatic EC cultures, oscillating shear stress-dependent induction of Cx37 expression required the presence of Foxc2 (Sabine et al, 2012). Moreover, it was recently demonstrated that conditional ablation of Cdk5, an activator of Foxc2 activity, greatly decreased Cx37 expression in lymphatic vessels (Liebl et al, 2015), and that knockdown of GATA2, which is upstream of Foxc2, blocked the flow-induced expression of Cx37 (Sweet et al, 2015). Furthermore, in the Foxc2 +/− Cx37 +/− mice generated in this study, there was significant inhibition of BV valve formation, consistent with a genetic interaction between Foxc2 and Cx37 .…”

Section: Discussionmentioning

confidence: 99%

Segregated Foxc2, NFATc1 and Connexin expression at normal developing venous valves, and Connexin-specific differences in the valve phenotypes of Cx37, Cx43, and Cx47 knockout mice

Munger

Geng

Srinivasan

et al. 2016

Developmental Biology

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Venous valves (VVs) are critical for unidirectional blood flow from superficial and deep veins towards the heart. Congenital valve aplasia or agenesis may, in some cases, be a direct cause of vascular disease, motivating an understanding of the molecular mechanisms underlying the development and maintenance of VVs. Three gap junction proteins (Connexins), Cx37, Cx43, and Cx47, are specifically expressed at VVs in a highly polarized fashion. VVs are absent from adult mice lacking Cx37; however it is not known if Cx37 is required for the initial formation of valves. In addition, the requirement of Cx43 and Cx47 for VV development has not been studied. Here, we provide a detailed description of Cx37, Cx43, and Cx47 expression during mouse vein development and show by gene knockout that each Cx is necessary for normal valve development. The valve phenotypes in the knockout lines exhibit Cx-specific differences, however, including whether peripheral or central VVs are affected by gene inactivation. In addition, we show that a Cx47 null mutation impairs peripheral VV development but does not affect lymphatic valve formation, a finding of significance for understanding how some CX47 mutations cause inherited lymphedema in humans. Finally, we demonstrate a striking segregation of Foxc2 and NFATc1 transcription factor expression between the downstream and upstream faces, respectively, of developing VV leaflets and show that this segregation is closely associated with the highly polarized expression of Cx37, Cx43, and Cx47. The partition of Foxc2 and NFATc1 expression at VV leaflets makes it unlikely that these factors directly cooperate during the leaflet elongation stage of VV development.

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Section: Discussionmentioning

confidence: 99%

Segregated Foxc2, NFATc1 and Connexin expression at normal developing venous valves, and Connexin-specific differences in the valve phenotypes of Cx37, Cx43, and Cx47 knockout mice

Munger

Geng

Srinivasan

et al. 2016

Developmental Biology

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“…Foxc2 activity is also regulated by cyclin-dependent kinase 5 (Cdk5) by phosphorylation at serine/threonine residues. Endothelial cell specific deletion of Cdk5 leads to blood-filled dilated lymphatic vessels and edema (603). Besides Foxc2 , the Reln gene that encodes the protein reelin is also critical for the maturation of collecting lymphatic vessels.…”

Section: Development Of Lymphatic Vessel Networkmentioning

confidence: 99%

Lymphatic Vessel Network Structure and Physiology

Breslin

Yang

Scallan

et al. 2018

Comprehensive Physiology

243

258

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The lymphatic system is comprised of a network of vessels interrelated with lymphoid tissue, which has the holistic function to maintain the local physiologic environment for every cell in all tissues of the body. The lymphatic system maintains extracellular fluid homeostasis favorable for optimal tissue function, removing substances that arise due to metabolism or cell death, and optimizing immunity against bacteria, viruses, parasites, and other antigens. This article provides a comprehensive review of important findings over the past century along with recent advances in the understanding of the anatomy and physiology of lymphatic vessels, including tissue/organ specificity, development, mechanisms of lymph formation and transport, lymphangiogenesis, and the roles of lymphatics in disease.

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“…Furthermore other potential downstream targets of Cdk5 with funtion in angiogenesis, such as HIF1α and Notch, are being identified [46, 49]. With the recent discovery that Cdk5 is involved in the development of lymphatic vessels [52], it is becoming clear that Cdk5 plays a more important role than suspected in the tumor vasculature and in supporting tumor development and spread.…”

Section: An Unexpected Role For Cdk5 In Tumor Angiogenesismentioning

confidence: 99%

The Emerging Role of Cdk5 in Cancer

2016

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Cdk5 is an atypical cyclin-dependent kinase that is well characterized for its role in the central nervous system rather than in the cell cycle. However Cdk5 has been recently implicated in the development and progression of a variety of cancers including breast, lung, colon, pancreatic, melanoma, thyroid and brain tumors. This broad pro-tumorigenic role makes Cdk5 a promising drug target for the development of new cancer therapies. Here we review the contribution of Cdk5 to molecular mechanisms that confer upon tumors the ability to grow, proliferate and disseminate to secondary organs, as well as resistance to chemotherapies. We subsequently discuss existing and new strategies for targeting Cdk5 and its downstream mechanisms as anti-cancer treatments.

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Cdk5 controls lymphatic vessel development and function by phosphorylation of Foxc2

Cited by 41 publications

References 45 publications

Segregated Foxc2, NFATc1 and Connexin expression at normal developing venous valves, and Connexin-specific differences in the valve phenotypes of Cx37, Cx43, and Cx47 knockout mice

Segregated Foxc2, NFATc1 and Connexin expression at normal developing venous valves, and Connexin-specific differences in the valve phenotypes of Cx37, Cx43, and Cx47 knockout mice

Lymphatic Vessel Network Structure and Physiology

The Emerging Role of Cdk5 in Cancer

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