Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43

Stephanie J. Munger, Michael J. Davis, Alex Simon

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Lymphatic valves (LVs) are cusped luminal structures that permit the movement of lymph in only one direction and are therefore critical for proper lymphatic vessel function. Congenital valve aplasia or agenesis can, in some cases, be a direct cause of lymphatic disease. Knowledge about the molecular mechanisms operating during the development and maintenance of LVs may thus aid in the establishment of novel therapeutic approaches to treat lymphatic disorders. In this study, we examined the role of Connexin43 (Cx43), a gap junction protein expressed in lymphatic endothelial cells (LECs), during valve development. Mouse embryos with a null mutation in Cx43 (Gja1) were previously shown to completely lack mesenteric LVs at embryonic day 18. However, interpreting the phenotype of Cx43-/- mice was complicated by the fact that global deletion of Cx43 causes perinatal death due to heart defects during embryogenesis. We have now generated a mouse model (Cx43∆LEC) with a lymphatic-specific ablation of Cx43 and show that the absence of Cx43 in LECs causes a delay (rather than a complete block) in LV initiation, an increase in immature valves with incomplete leaflet elongation, a reduction in the total number of valves, and altered lymphatic capillary patterning. The physiological consequences of these lymphatic changes were leaky valves, insufficient lymph transport and reflux, and a high incidence of lethal chylothorax. These results demonstrate that the expression of Cx43 is specifically required in LECs for normal development of LVs.

Original languageEnglish (US)
Pages (from-to)204-218
Number of pages15
JournalDevelopmental Biology
Volume421
Issue number2
DOIs
StatePublished - Jan 15 2017

Fingerprint

Chylothorax
Connexin 43
Lymphatic Vessels
Endothelial Cells
Lymph
Connexins
Lymphatic Diseases
Embryonic Development
Cause of Death
Embryonic Structures
Maintenance
Phenotype
Mutation
Incidence

Keywords

  • Chylothorax
  • Connexin
  • Connexin43
  • Gap junction
  • Lymphatic valve
  • Valve development

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43. / Munger, Stephanie J.; Davis, Michael J.; Simon, Alex.

In: Developmental Biology, Vol. 421, No. 2, 15.01.2017, p. 204-218.

Research output: Contribution to journalArticle

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