Abnormal embryonic lymphatic vessel development in Tie1 hypomorphic mice.
Tie1 is an endothelial receptor tyrosine kinase that is essential for development and maintenance of the vascular system; however, the role of Tie1 in development of the lymphatic vasculature is unknown. To address this question, we first documented that Tie1 is expressed at the earliest stages of lymphangiogenesis in Prox1-positive venous lymphatic endothelial cell (LEC) progenitors. LEC Tie1 expression is maintained throughout embryonic development and persists in postnatal mice. We then generated two lines of Tie1 mutant mice: a hypomorphic allele, which has reduced expression of Tie1, and a conditional allele. Reduction of Tie1 levels resulted in abnormal lymphatic patterning and in dilated and disorganized lymphatic vessels in all tissues examined and in impaired lymphatic drainage in embryonic skin. Homozygous hypomorphic mice also exhibited abnormally dilated jugular lymphatic vessels due to increased production of Prox1-positive LECs during initial lymphangiogenesis, indicating that Tie1 is required for the early stages of normal lymphangiogenesis. During later stages of lymphatic development, we observed an increase in LEC apoptosis in the hypomorphic embryos after mid-gestation that was associated with abnormal regression of the lymphatic vasculature. Therefore, Tie1 is required for early LEC proliferation and subsequent survival of developing LECs. The severity of the phenotypes observed correlated with the expression levels of Tie1, confirming a dosage dependence for Tie1 in LEC integrity and survival. No defects were observed in the arterial or venous vasculature. These results suggest that the developing lymphatic vasculature is particularly sensitive to alterations in Tie1 expression.
Division of Pediatric Cardiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Xianghu
X
Qu
Kevin
K
Tompkins
Lorene E
LE
Batts
Mira
M
Puri
H Scott
HS
Baldwin
Scott
S
Baldwin
D000818:Animals; D017209:Apoptosis; D001808:Blood Vessels / Q000196:embryology / Q000502:physiology; D017931:DNA Primers; D015342:DNA Probes; D047108:Embryonic Development / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D042583:Lymphangiogenesis / Q000235:genetics* / Q000502:physiology; D008208:Lymphatic System / Q000196:embryology* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics; D042764:Receptors, TIE / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D015342:DNA Probes; D020794:Receptor Protein-Tyrosine Kinases; D042764:Receptors, TIE