Table 1.
Knockout mouse models and associated lymphatic phenotypes.
| Gene of Interest | Mutant Mouse Models and Observations | Proposed function |
|---|---|---|
| Lymphatic Phenotypes Reported in Knockout Mouse Models | ||
| Prox1 | A) Global Prox1+/−: Reduction in LEC number followed with the loss of lymphovenous valves (13). Severe edema is detected at mid-gestation stage at E14.5. Most die within 2–3 days after birth, presenting chylous ascites (14). Surviving mice maintain impaired lymphatic vasculature and encounter adult-onset obesity (15) B) Tie2-Cre; Prox1 fl/+: Same as A C) Global Prox1−/−: LEC specification lost and budding/sprouting arrested around E11.5, shortly after initiation; no lymphatic vasculature (7). Mice present severe edema and die around mid-gestation stage at E14.5–15 (7, 14) |
Prox1 is a master switch for LEC specification, maintenance as well as sprouting |
| Vegfc | A) Global Vegfc+/−: Embryo lymph sac formation was normal or slightly reduced. Severe lymphatic vessel hypoplasia accompanied by chylous ascites in pups, with some recovery in first postnatal weeks. Cutaneous lymphatic vessel hypoplasia remained in skin of adults (16) B) Global Vegfc−/−: LECs unable to sprout and form lymphatic vessels. Severe edema from E12.5 onward. Embryonic death with half of embryos dying E15.5–E17.5. No live-born pups (16) |
Key growth factor for Vegfr3 and thereby AKT and ERK signaling |
| Vegfr3 | A) Global Vegfr3+/−: Embryos appear phenotypically normal (17). Lymphedema due to hypoplastic cutaneous lymphatic vessels (18) B) Global Vegfr3−/−: Embryonic death beginning at E10.5, prior to lymphatic vessel emergence/sprouting. No live-born pups (17). Abnormal vasculature, enlarged vascular bed formation, severe anemia before embryonic death (19) |
Receptor for growth factors to initiate AKT and ERK signaling almost exclusively in LECs, though present in other ECs during early development |
| Foxc1/2 | A) Global Foxc1−/−: Increased LEC specification and proliferation. Enlarged lymph sacs at E12.5. Subcutaneous edema from E15.5 onward with lymphatic vessel hyperplasia (20) B) Prox1CreERT2; Foxc1fl/fl: Same as A C) Prox1CreERT2; Foxc2fl/fl Same as A D) Prox1CreERT2;Foxc1fl/fl/Foxc2fl/fl Similar to A, but with ~5% rate of severe edema at E15.5 (20) |
Foxc1 promotes the expression of GTPase-activating proteins that are coded by Rasal3 and Rasa4 to regulate the ERK pathway (20) |
| Ras | A) Global Ras TKO: Decreased lymphatic specification. Embryonic lethality B) Global Ras DKO: Pups presented chylous ascites and lymphatic vessel hypoplasia (21) |
Ras is a major effector protein involved in AKT and ERK signaling (21) |
| Rasa1 | A) Ub-CreERT2; Rasa1fl/fl: Following tamoxifen injection at 2 months of age, mice presented chylous ascites, lymphatic vessel dilation and extensive lymphatic vessel hyperplasia. All mice died by 8 months after tamoxifen administration (22) | Rasa1 codes a negative regulator of vascular growth (22). Rasa1 may modulate AKT and ERK signaling by turning off Ras |
| Akt1 | A) Global Akt1−/−: Enlargement of collecting lymphatic vessels, increased number of LECs, sparse coverage of smooth muscle cells. Loss of valves in small collecting lymphatics in bottom side of ear skin (23) | Akt1 a protein kinase that acts as a major signal transducer involved in both blood and lymphatic vascular development (23) |
| Spred-1/2 | A) Global Spred-1−/+/Spred-2−/+: Mice are healthy and fertile (24) B) Global Spred-1−/−/Spred-2−/−: Embryonic death between E12.5–15.5 with severe subcutaneous hemorrhage, edema, and dilated lymph vessels. Blood vessels appear almost normal when compared to controls (24) C) Global Spred-1−/−/Spred-2−/+:Similar bleeding as A. Mice rarely born and most died within a few months (24) D) Global Spred-1−/+/Spred-2−/−:Mice were healthy and fertile, but smaller than mice described in A (24) |
Spred-1 and Spred-2 are negative regulators in VEGF-C/VEGFR-3 signaling, inhibiting ERK and AKT activity (24) |
| Cdh5 | A) Prox1CreERT2; Cdh5fl/fl: Following tamoxifen injection at E10: Dilated lymphatic vessels in mesentery, valves still absent by E18.5. Edema observed at E14.5 and onward. Pups presented chylous ascites (25) B) Global Cdh5−/−: Embryonic death at E9.5 (26) |
VE-Cadherin required for response to fluid shear stress and thereby Beta-Catenin and AKT signaling, promoting Prox1 and Foxc2 expression (25) |
These models tend to lead to loss of proper vascular development, typically manifested as edema in varying severity with the potential for embryonic death.