TY - JOUR
T1 - Connexin37 and Connexin43 deficiencies in mice disrupt lymphatic valve development and result in lymphatic disorders including lymphedema and chylothorax
AU - Kanady, John D.
AU - Dellinger, Michael T.
AU - Munger, Stephanie J.
AU - Witte, Marlys H.
AU - Simon, Alexander M.
N1 - Funding Information:
We thank Gerald Kidder for Cx43+/− mice, Naoyuki Miura for Foxc2+/− mice, Paul Lampe for Cx26 antibody, David Paul for Cx40 antibody, and Robert Erickson for comments on the manuscript. We thank Caterina Sellito for assistance with the Cx37−/−Cx43+/− mice in the early stages of this work. This work was supported by NIH grant HL64232 to A.M. Simon. MT Dellinger was supported by Arizona Disease Control Research Commission Contract 9002 (Robert P. Erickson).
PY - 2011/6/15
Y1 - 2011/6/15
N2 - Intraluminal valves are required for the proper function of lymphatic collecting vessels and large lymphatic trunks like the thoracic duct. Despite recent progress in the study of lymphvasculogenesis and lymphangiogenesis, the molecular mechanisms controlling the morphogenesis of lymphatic valves remain poorly understood. Here, we report that gap junction proteins, or connexins (Cxs), are required for lymphatic valvulogenesis. Cx37 and Cx43 are expressed early in mouse lymphatic development in the jugular lymph sacs, and later in development these Cxs become enriched and differentially expressed by lymphatic endothelial cells on the upstream and downstream sides of the valves. Specific deficiencies of Cx37 and Cx43 alone or in combination result in defective valve formation in lymphatic collecting vessels, lymphedema, and chylothorax. We also show that Cx37 regulates jugular lymph sac size and that both Cx37 and Cx43 are required for normal thoracic duct development, including valve formation. Another Cx family member, Cx47, whose human analog is mutated in some families with lymphedema, is also highly enriched in a subset of endothelial cells in lymphatic valves. Mechanistically, we present data from Foxc2-/- embryos suggesting that Cx37 may be a target of regulation by Foxc2, a transcription factor that is mutated in human lymphedema-distichiasis syndrome. These results show that at least three Cxs are expressed in the developing lymphatic vasculature and, when defective, are associated with clinically manifest lymphatic disorders in mice and man.
AB - Intraluminal valves are required for the proper function of lymphatic collecting vessels and large lymphatic trunks like the thoracic duct. Despite recent progress in the study of lymphvasculogenesis and lymphangiogenesis, the molecular mechanisms controlling the morphogenesis of lymphatic valves remain poorly understood. Here, we report that gap junction proteins, or connexins (Cxs), are required for lymphatic valvulogenesis. Cx37 and Cx43 are expressed early in mouse lymphatic development in the jugular lymph sacs, and later in development these Cxs become enriched and differentially expressed by lymphatic endothelial cells on the upstream and downstream sides of the valves. Specific deficiencies of Cx37 and Cx43 alone or in combination result in defective valve formation in lymphatic collecting vessels, lymphedema, and chylothorax. We also show that Cx37 regulates jugular lymph sac size and that both Cx37 and Cx43 are required for normal thoracic duct development, including valve formation. Another Cx family member, Cx47, whose human analog is mutated in some families with lymphedema, is also highly enriched in a subset of endothelial cells in lymphatic valves. Mechanistically, we present data from Foxc2-/- embryos suggesting that Cx37 may be a target of regulation by Foxc2, a transcription factor that is mutated in human lymphedema-distichiasis syndrome. These results show that at least three Cxs are expressed in the developing lymphatic vasculature and, when defective, are associated with clinically manifest lymphatic disorders in mice and man.
KW - Chylothorax
KW - Connexin
KW - Gap junction
KW - Lymphatic development
KW - Lymphedema
KW - Valvulogenesis
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U2 - 10.1016/j.ydbio.2011.04.004
DO - 10.1016/j.ydbio.2011.04.004
M3 - Article
C2 - 21515254
AN - SCOPUS:79955954437
SN - 0012-1606
VL - 354
SP - 253
EP - 266
JO - Developmental Biology
JF - Developmental Biology
IS - 2
ER -