Table 2.
Murine knockout models and their lymphatic phenotypes reveal gene functions in lymphangiogenesis
| Murine Model | Lethality | Lymphatic Phenotype | Gene Function | Reference(s) |
|---|---|---|---|---|
| Prox-1 | ||||
| Prox1+/− | P2–P3 | Abdominal chylous ascites. Detectable but dysfunctional lymphatic vessels. | Prox-1 is required for the maintenance of lymphatic cell budding and sprouting and is critical in BEC commitment to LECs. | 55; 78; 8 |
| Prox1−/− | E14.5 | Arrested sprouting with no lymphatic vessels present. Venous ECs lack lymphatic markers LYVE-1 and SLC but contain blood markers CD34 and laminin. | ||
| SRY-related HMG-box 18 (Sox18) | ||||
| Sox18+/− | Normal | Fine, dense, and more branched lymphatic vessels. | Sox18 is a transcription factor that is responsible for inducing the expression of Prox-1 on lymphatic vasculature precursor cells. | 84; 85 |
| Sox18−/− | 14.5 d.p.c. | No lymphatic vessels present. No venous Prox-1 expression. | ||
| Vascular endothelial growth factors C and D (VEGF-C and VEGF-D) | ||||
| Vegfc+/− | Normal or perinatal | Abdominal chylous ascites. Cutaneous lymphatic hypoplasia with lymphedema in adults. | VEGF-C controls the process of Prox-1– positive LEC sprouting and migration from embryonic veins. VEGF-C is required for LEC proliferation and survival. VEGFD plays a similar but not as impactful role as VEGF-C. | 42; 87 |
| Vegfc−/− | E17–E19 | No detected lymphatic vessels. Severe embryonic lymphedema. | ||
| Vegfd−/− | Normal | Normal lymphatic vasculature. | ||
| Vegfc−/− x Vegfd−/− | E16.5 | Same phenotype as Vegfc−/−. | ||
| Vascular endothelial growth factor receptor 3 (VEGFR-3) | ||||
| Vegfr3+/neo | Normal | Leaky and dysfunctional lymphatic vessels. Transient abdominal chylous ascites after birth. | VEGFR-3 is regulated by VEGF-C and VEGF-D and is necessary for LEC proliferation and survival. VEGFR-3 is also necessary for angiogenesis. | 42; 148 |
| Vegfr3neo/neo | Perinatal | No detectable lymphatic vessels. Cardiovascular failure. | ||
| Vegfr3lz/lz | E10.5 | No detectable lymphatic vessels. | ||
| Podoplanin | ||||
| T1α/podoplanin+/− | Normal | Similar to wild-type mice. Some regions of dilated lymphatic vessels with incomplete lymphatic network formation. | Podoplanin plays a critical role in lymphatic patterning and network formation. Specifically, podoplanin promotes LEC migration, adhesion, and tubulogenesis. | 98; 100 |
| T1α/podoplanin−/− | Perinatal | Congenital lymph edema, impaired lymphatic transport, lymphangiectasia, undetectable small lymphatic capillaries, absent abdominal lacteals, and lack of anatamosing lymphatic vessels between superficial and subcutaneous lymphatic networks. Incomplete separation between blood vascular and lymphatic vascular systems. | ||
| Angiopoietin 2 (Ang2) | ||||
| Ang2+/− | Normal | Collecting lymphatics with valves are present. Needs additional investigation. | Ang2 is required for the remodeling and maturation of the primary lymphatic plexus. This includes the emergence of a secondary lymphatic plexus along with the development of collecting lymphatic vessels with valves. | 108; 110 |
| Ang2−/− | Perinatal or normal | Abdominal chylous ascites and chylothorax. Lymphedema present. Lack of collecting lymphatic vessels with valves. Primary and secondary lymphatic plexus hypoplasia. Impaired lymphatic maturation and remodeling. | ||
| EphrinB2 | ||||
| EphrinB2ΔV/ΔV | Perinatal | No lymphatic valves. Chylothorax. | EphrinB2 is essential in regulating valve formation and morphology in developing lymphatics. Data regarding whether ephrinB2 forward or reverse signaling is responsible for valve formation are conflicting. | 111; 114; 122 |
| EphrinB26YFΔV/6YFΔV | Perinatal | No lymphatic valves. Chylothorax. | ||
| EphrinB2lacZ/lacZ | Perinatal | Normal lymphatic valves detected at E18. | ||
| EphrinB26YFΔV/lacZ | Normal | Normal lymphatic development. | ||
| Forkhead box c2 (Foxc2) | ||||
| Foxc2+/− | Normal | Lymphatic hyperplasia and reflux. Distichiasis. | Foxc2 is necessary for the lymphatic vessel maturation and valve formation. | 125; 127; 130; 131; 132 |
| Foxc2−/− | E12.5 | Cardiovascular and skeletal defects. Impaired lymphatic maturation, remodeling, and valve formation. | ||
| Neuropilin-2 (NRP2) | ||||
| Nrp2+/− | Normal | Appears unaffected. | Nrp2 is necessary for new lymphatic vessels sprouting from pre-existing lymphatic vessels. Nrp2 inhibits tip cell retraction and thus promotes VEGF-C induced tip cell extension from the lymphatic sprout. | 94; 136; 138 |
| Nrp2+/−vegfr3+/− | Reduced Mendelian ratio | Lymphatic hypoplasia in the skin with lymphatic vessel enlargement and increased branching. Reduced number of tip cells with defective filopodia extension from existing tip cells. Enlarged lymph sac and severe edema present. | ||
| Nrp2−/− | Reduced Mendelian ratio | |||
| SLP-76 and Syk | ||||
| Slp-76−/− or Syk−/− | Perinatal | Nonseparation phenotype. Chylous ascites. Lymphatic vessels are filled with blood. | Slp-76 and Syk are hematopoietic intracellular signaling proteins required for the separation of the closed blood vascularsystem from the open lymphatic system. | 142; 143 |
| C-type lectin-like receptor 2 (CLEC-2) | ||||
| Clec-2+/− | Normal | Normal | CLEC-2 serves as the intermediate between podoplanin and SLP-76/Syk. LEC podoplanin binds to CLEC-2 to activate platelet cells and induce release of granules that inhibit lymphangiogenesis. | 100; 101; 145; 146 |
| Clec-2−/− | Perinatal | Nonseparation phenotype. | ||
| Elk3 (Net) | ||||
| Elk3−/− | Perinatal | Chylothorax and lymphangiectasis. | N/A | 147 |
| Integrin α9 | ||||
| α9−/− | Perinatal | Chylothorax and lymphangiectasis. | Integrin-α9 binds to VEGF-C and VEGF-D and also interacts with VEGFR-3. | 149; 150 |