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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

Identifieur interne : 000B40 ( Main/Exploration ); précédent : 000B39; suivant : 000B41

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

Auteurs : Stephanie J. Munger [États-Unis] ; Xin Geng [États-Unis] ; R. Sathish Srinivasan [États-Unis] ; Marlys H. Witte [États-Unis] ; David L. Paul [États-Unis] ; Alexander M. Simon [États-Unis]

Source :

RBID : PMC:4826804

Descripteurs français

English descriptors

Abstract

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.


Url:
DOI: 10.1016/j.ydbio.2016.02.033
PubMed: 26953188
PubMed Central: 4826804


Affiliations:


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<term>Animals</term>
<term>Connexin 43 (genetics)</term>
<term>Connexin 43 (metabolism)</term>
<term>Connexins (genetics)</term>
<term>Connexins (metabolism)</term>
<term>Forkhead Transcription Factors (genetics)</term>
<term>Forkhead Transcription Factors (metabolism)</term>
<term>Immunohistochemistry</term>
<term>Mice, Inbred C57BL</term>
<term>Mice, Knockout</term>
<term>NFATC Transcription Factors (genetics)</term>
<term>NFATC Transcription Factors (metabolism)</term>
<term>Phenotype</term>
<term>Time Factors</term>
<term>Venous Valves (embryology)</term>
<term>Venous Valves (growth & development)</term>
<term>Venous Valves (metabolism)</term>
</keywords>
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<term>Animaux</term>
<term>Connexine 43 (génétique)</term>
<term>Connexine 43 (métabolisme)</term>
<term>Connexines (génétique)</term>
<term>Connexines (métabolisme)</term>
<term>Facteurs de transcription Forkhead (génétique)</term>
<term>Facteurs de transcription Forkhead (métabolisme)</term>
<term>Facteurs de transcription NFATC (génétique)</term>
<term>Facteurs de transcription NFATC (métabolisme)</term>
<term>Facteurs temps</term>
<term>Immunohistochimie</term>
<term>Phénotype</term>
<term>Souris de lignée C57BL</term>
<term>Souris knockout</term>
<term>Valves veineuses (croissance et développement)</term>
<term>Valves veineuses (embryologie)</term>
<term>Valves veineuses (métabolisme)</term>
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<term>Connexin 43</term>
<term>Connexins</term>
<term>Forkhead Transcription Factors</term>
<term>NFATC Transcription Factors</term>
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<term>Connexin 43</term>
<term>Connexins</term>
<term>Forkhead Transcription Factors</term>
<term>NFATC Transcription Factors</term>
</keywords>
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<term>Valves veineuses</term>
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<term>Venous Valves</term>
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<term>Venous Valves</term>
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<term>Connexines</term>
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<term>Facteurs de transcription NFATC</term>
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<p id="P1">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
<italic>Cx47</italic>
null mutation impairs peripheral VV development but does not affect lymphatic valve formation, a finding of significance for understanding how some
<italic>CX47</italic>
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.</p>
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