Knockout or mutant mouse models and their phenotypes according to stages of lymphatic vascular morphogenesis
| Gene symbol | Function | Lymphatic vascular phenotype | Expression pattern |
| LEC differentiation | |||
| Prox1 | Transcription factor | No LECs (−/−), chylous ascites (+/−); loss of LEC identity, chylous ascites, obesity (Prox1f/f; Tie2-Cre; Wigle et al., 1999; Harvey et al., 2005; Johnson et al., 2008) | LECs, hepatocytes, lens fiber cells, pancreatic, lung, and intestinal endocrine cells, skeletal muscle, cardiomyocytes |
| Sox18 | Transcription factor | No LECs(−/−, on C57BL/6J background); abnormal patterning (+/−); edema and chylous ascites (heterozygous ragged mutants; Pennisi et al., 2000; François et al., 2008) | Endothelial cells |
| Coup-TFII (NR2F2) | Transcription factor | No LECs (−/−, deletion at or before E9.5); edema, loss of LEC identity, and sprouting (−/−, deletion at later stages; Lin et al., 2010; Srinivasan et al., 2010) | Endothelial cells and SMCs |
| Lymphangiogenesis | |||
| Vegf-c–Vegfr-3 pathway | |||
| Vegfr3 | Receptor tyrosine kinase | Hypoplasia, chylous ascites (+/Chy, ENU-induced mutation, loss of tyrosine kinase activity; Karkkainen et al., 2001); lymph sacs formed and defective sprouting (homozygous deletion of ligand-binding domain; Zhang et al., 2010) | LECs, fenestrated blood vascular endothelial cells, blood vascular endothelial cells in tumors and during early embryogenesis |
| Vegfc | Growth factor, ligand for Vegfr-3 | No sprouting of LECs from veins (−/−); hypoplasia, chylous ascites (+/−; Karkkainen et al., 2003) | Macrophages, SMCs, and subpopulation of mesenchymal cells during development |
| Nrp2 | Coreceptor of Vegfr-3 and semaphorins | Transient capillary hypoplasia, defective sprouting (−/−; Yuan et al., 2002; Xu et al., 2010) | Venous and lymphatic endothelial cells |
| Rac1 | Rho GTPase | Abnormal migration of LECs from veins (Rac1f/f; Tie1-Cre; D’Amico et al., 2009) | Broad |
| Clp24 | Transmembrane protein | Lymphangiectasia, ectopic mural cells (Clp24−/−; Clp24−/−; Vegfr3lacz/+ and Clp24−/−; Vegfr2lacz/+; Saharinen et al., 2010) | Endothelial cells |
| Tbx1 | Transcription factor | Hypoplasia and chylous ascites (Tbx1f/f; Tie2-Cre; Chen et al., 2010) | Vascular, including LECs |
| Ptpn14 (gene trap) | Protein tyrosine phosphatase | Hyperplasia of dermal lymphatic vessels in 14% of mutants, paw or periorbital edema (Au et al., 2010) | Broad, including LECs |
| Adrenomedullin signaling | |||
| Adm (adrenomedullin) | Peptide vasodilator, ligand for Calcrl | Hypoplasia of jugular lymph sacs, decreased LEC proliferation, edema (−/−, CalcrlLoxP/–;Tie2-Cre; Fritz-Six et al., 2008) | Adrenal medulla, vascular SMCs and endothelial cells, cardiomyocytes |
| Ramp2 | Coreceptor of Calcrl | Hypoplasia of jugular lymph sacs, decreased LEC proliferation, edema (−/−, CalcrlLoxP/–;Tie2-Cre; Fritz-Six et al., 2008) | Broad, including LECs |
| Calcrl (calcitonin receptor-like) | G protein–coupled receptor of adrenomedullin | Hypoplasia of jugular lymph sacs, decreased LEC proliferation, edema (−/−, CalcrlLoxP/–;Tie2-Cre; Fritz-Six et al., 2008) | Broad, including LECs |
| Other | |||
| Vezf | Transcription factor | Transient jugular lymphatic hypervascularization (+/−; Kuhnert et al., 2005) | Broad |
| Tie1 | Receptor tyrosine kinase | Abnormal lymphatic patterning, dilated and disorganized lymphatic vessels (hypomorphic mice on outbred background; D’Amico et al., 2010) | Endothelial and hematopoietic cells |
| Separation of blood and lymphatic vessels | |||
| Platelet development | |||
| Meis1 | Transcription factor | Blood-filled lymphatic vessels (−/−; Carramolino et al., 2010) | Broad, including developing hematopoietic cells |
| Platelet aggregation | |||
| Slp76 | Adaptor protein | Blood-filled lymphatic vessels, chylous ascites (−/−; Abtahian et al., 2003) | Hematopoietic cells |
| Plcg2 | Phospholipase C, hydrolysis of phospholipids | Blood-filled lymphatic vessels, chylous ascites (−/−; Ichise et al., 2009) | Broad |
| Pdpn (podoplanin) | Transmembrane glycoprotein | Lymphangiectasia, abnormal lymph transport, lymphedema, blood-filled lymphatic vessels (−/−; Schacht et al., 2003; Bertozzi et al., 2010; Uhrin et al., 2010) | LECs, keratinocytes, alveolar type II cells, podocytes |
| C1galt1 (encodes T-synthetase) | Glycosyltransferase, biosynthesis of core-1–derived O-glycans | Blood-filled lymphatic vessels, decreased levels of podoplanin (−/−; Fu et al., 2008) | Endothelial and hematopoietic cells |
| Clec-2 | C-type lectin receptor | Blood-filled lymphatic vessels (−/−; Bertozzi et al., 2010; Suzuki-Inoue et al., 2010) | Platelets, peripheral blood neutrophils |
| Syk | Nonreceptor tyrosine kinase | Blood-filled lymphatic vessels, chylous ascites, accumulation of myeloid cells in the dermis (−/−, Sykf/f;vav-cre; Abtahian et al., 2003; Bertozzi et al., 2010; Böhmer et al., 2010) | |
| Other | |||
| Spred1/Spred2 | Cytoplasmic adaptor proteins | Blood-filled lymphatic vessels (Spred1−/−; Spred2−/−; Taniguchi et al., 2007) | Broad, including LECs |
| Remodeling, maturation, and valve morphogenesis | |||
| Tie/PI3-kinase signaling | |||
| Akt1 | Ser/Thr kinase | Capillary hypoplasia, valve agenesis, dilation, and decreased SMC coverage of small collecting lymphatic vessels (−/−; Zhou et al., 2010) | Broad |
| Angpt2 | Growth factor, ligand of Tie receptor tyrosine kinases | Hypoplasia, chylous ascites, defective remodeling, and valve agenesis (−/−; Gale et al., 2002; Dellinger et al., 2008) | (Lymph) angiogenenic endothelial cells, hematopoietic cells |
| Pi3kca (mutation blocking interaction with Ras) | Catalytic p110α isoform of PI3-kinase | Chylous ascites, hypoplasia, impaired sprouting, and branching of lymphatic capillaries (−/−; Gupta et al., 2007) | Broad |
| Pik3r1 | Regulatory subunits of class IA PI3-kinases | Chylous ascites, intestinal lymphangiectasia, impaired sprouting, lymphatic, valve agenesis (−/−; Mouta-Bellum et al., 2009) | Broad |
| ECM assembly and interactions | |||
| Itga9 | Adhesion | Chylothorax, lymphatic valve agenesis (−/−; Itga9f/f; Tie2-Cre and Itga9f/f; Cdh5 (PAC)-CreERT2; Bazigou et al., 2009) | BECs and LECs (highest in valves), vascular SMCs |
| Fn1 (removal of EDA domain) | ECM component, ligand of Itg-α9 | Failure of lymphatic valve leaflet elongation (−/−; Bazigou et al., 2009) | Broad, including lymphatic valves |
| Emilin1 | Elastic microfibril-associated protein | Hyperplasia and abnormal patterning of lymphatic vessels, reduction of anchoring filaments; impaired lymph drainage, increased lymph leakage (−/−; Danussi et al., 2008) | Broad, including LECs |
| Other | |||
| Aspp1 | Cytoplasmic adaptor protein | Impaired assembly of lymphatic vessels and collecting lymphatic vessel patterning, accumulation of « lymphatic islands » (−/−; Hirashima et al., 2008) | Endothelial cells |
| Efnb2 (mutation of PDZ binding site) | Ligand of EphB receptor tyrosine kinases | Impaired sprouting of capillaries, agenesis of lymphatic valves, ectopic mural cells, chylothorax, retrograde lymph flow (−/−; Mäkinen et al., 2005) | Arterial endothelial cells and SMCs, LECs (highest in the valves) |
| Foxc2 | Transcription factor | Impaired patterning of capillaries, no collecting lymphatic vessels, agenesis of lymphatic valves, ectopic mural cells, retrograde lymph flow (−/−; Dagenais et al., 2004; Petrova et al., 2004; Norrmén et al., 2009) | Arterial endothelial cells and SMCs, LECs (highest in the valves) |
| Elk3 (Net) | Transcription factor | Lymphangiectasia, chylothorax (−/−; Ayadi et al., 2001) | Endothelial cells |
| PU.1 Csfr1 | Transcription factor receptor for M-CSF1 | Hyperplasia and abnormal patterning of dermal lymphatic vessels (−/−; Gordon et al., 2010) | Hematopoietic cells (stage dependent) |
| Gene symbol | Function | Lymphatic vascular phenotype | Expression pattern |
| LEC differentiation | |||
| Prox1 | Transcription factor | No LECs (−/−), chylous ascites (+/−); loss of LEC identity, chylous ascites, obesity (Prox1f/f; Tie2-Cre; Wigle et al., 1999; Harvey et al., 2005; Johnson et al., 2008) | LECs, hepatocytes, lens fiber cells, pancreatic, lung, and intestinal endocrine cells, skeletal muscle, cardiomyocytes |
| Sox18 | Transcription factor | No LECs(−/−, on C57BL/6J background); abnormal patterning (+/−); edema and chylous ascites (heterozygous ragged mutants; Pennisi et al., 2000; François et al., 2008) | Endothelial cells |
| Coup-TFII (NR2F2) | Transcription factor | No LECs (−/−, deletion at or before E9.5); edema, loss of LEC identity, and sprouting (−/−, deletion at later stages; Lin et al., 2010; Srinivasan et al., 2010) | Endothelial cells and SMCs |
| Lymphangiogenesis | |||
| Vegf-c–Vegfr-3 pathway | |||
| Vegfr3 | Receptor tyrosine kinase | Hypoplasia, chylous ascites (+/Chy, ENU-induced mutation, loss of tyrosine kinase activity; Karkkainen et al., 2001); lymph sacs formed and defective sprouting (homozygous deletion of ligand-binding domain; Zhang et al., 2010) | LECs, fenestrated blood vascular endothelial cells, blood vascular endothelial cells in tumors and during early embryogenesis |
| Vegfc | Growth factor, ligand for Vegfr-3 | No sprouting of LECs from veins (−/−); hypoplasia, chylous ascites (+/−; Karkkainen et al., 2003) | Macrophages, SMCs, and subpopulation of mesenchymal cells during development |
| Nrp2 | Coreceptor of Vegfr-3 and semaphorins | Transient capillary hypoplasia, defective sprouting (−/−; Yuan et al., 2002; Xu et al., 2010) | Venous and lymphatic endothelial cells |
| Rac1 | Rho GTPase | Abnormal migration of LECs from veins (Rac1f/f; Tie1-Cre; D’Amico et al., 2009) | Broad |
| Clp24 | Transmembrane protein | Lymphangiectasia, ectopic mural cells (Clp24−/−; Clp24−/−; Vegfr3lacz/+ and Clp24−/−; Vegfr2lacz/+; Saharinen et al., 2010) | Endothelial cells |
| Tbx1 | Transcription factor | Hypoplasia and chylous ascites (Tbx1f/f; Tie2-Cre; Chen et al., 2010) | Vascular, including LECs |
| Ptpn14 (gene trap) | Protein tyrosine phosphatase | Hyperplasia of dermal lymphatic vessels in 14% of mutants, paw or periorbital edema (Au et al., 2010) | Broad, including LECs |
| Adrenomedullin signaling | |||
| Adm (adrenomedullin) | Peptide vasodilator, ligand for Calcrl | Hypoplasia of jugular lymph sacs, decreased LEC proliferation, edema (−/−, CalcrlLoxP/–;Tie2-Cre; Fritz-Six et al., 2008) | Adrenal medulla, vascular SMCs and endothelial cells, cardiomyocytes |
| Ramp2 | Coreceptor of Calcrl | Hypoplasia of jugular lymph sacs, decreased LEC proliferation, edema (−/−, CalcrlLoxP/–;Tie2-Cre; Fritz-Six et al., 2008) | Broad, including LECs |
| Calcrl (calcitonin receptor-like) | G protein–coupled receptor of adrenomedullin | Hypoplasia of jugular lymph sacs, decreased LEC proliferation, edema (−/−, CalcrlLoxP/–;Tie2-Cre; Fritz-Six et al., 2008) | Broad, including LECs |
| Other | |||
| Vezf | Transcription factor | Transient jugular lymphatic hypervascularization (+/−; Kuhnert et al., 2005) | Broad |
| Tie1 | Receptor tyrosine kinase | Abnormal lymphatic patterning, dilated and disorganized lymphatic vessels (hypomorphic mice on outbred background; D’Amico et al., 2010) | Endothelial and hematopoietic cells |
| Separation of blood and lymphatic vessels | |||
| Platelet development | |||
| Meis1 | Transcription factor | Blood-filled lymphatic vessels (−/−; Carramolino et al., 2010) | Broad, including developing hematopoietic cells |
| Platelet aggregation | |||
| Slp76 | Adaptor protein | Blood-filled lymphatic vessels, chylous ascites (−/−; Abtahian et al., 2003) | Hematopoietic cells |
| Plcg2 | Phospholipase C, hydrolysis of phospholipids | Blood-filled lymphatic vessels, chylous ascites (−/−; Ichise et al., 2009) | Broad |
| Pdpn (podoplanin) | Transmembrane glycoprotein | Lymphangiectasia, abnormal lymph transport, lymphedema, blood-filled lymphatic vessels (−/−; Schacht et al., 2003; Bertozzi et al., 2010; Uhrin et al., 2010) | LECs, keratinocytes, alveolar type II cells, podocytes |
| C1galt1 (encodes T-synthetase) | Glycosyltransferase, biosynthesis of core-1–derived O-glycans | Blood-filled lymphatic vessels, decreased levels of podoplanin (−/−; Fu et al., 2008) | Endothelial and hematopoietic cells |
| Clec-2 | C-type lectin receptor | Blood-filled lymphatic vessels (−/−; Bertozzi et al., 2010; Suzuki-Inoue et al., 2010) | Platelets, peripheral blood neutrophils |
| Syk | Nonreceptor tyrosine kinase | Blood-filled lymphatic vessels, chylous ascites, accumulation of myeloid cells in the dermis (−/−, Sykf/f;vav-cre; Abtahian et al., 2003; Bertozzi et al., 2010; Böhmer et al., 2010) | |
| Other | |||
| Spred1/Spred2 | Cytoplasmic adaptor proteins | Blood-filled lymphatic vessels (Spred1−/−; Spred2−/−; Taniguchi et al., 2007) | Broad, including LECs |
| Remodeling, maturation, and valve morphogenesis | |||
| Tie/PI3-kinase signaling | |||
| Akt1 | Ser/Thr kinase | Capillary hypoplasia, valve agenesis, dilation, and decreased SMC coverage of small collecting lymphatic vessels (−/−; Zhou et al., 2010) | Broad |
| Angpt2 | Growth factor, ligand of Tie receptor tyrosine kinases | Hypoplasia, chylous ascites, defective remodeling, and valve agenesis (−/−; Gale et al., 2002; Dellinger et al., 2008) | (Lymph) angiogenenic endothelial cells, hematopoietic cells |
| Pi3kca (mutation blocking interaction with Ras) | Catalytic p110α isoform of PI3-kinase | Chylous ascites, hypoplasia, impaired sprouting, and branching of lymphatic capillaries (−/−; Gupta et al., 2007) | Broad |
| Pik3r1 | Regulatory subunits of class IA PI3-kinases | Chylous ascites, intestinal lymphangiectasia, impaired sprouting, lymphatic, valve agenesis (−/−; Mouta-Bellum et al., 2009) | Broad |
| ECM assembly and interactions | |||
| Itga9 | Adhesion | Chylothorax, lymphatic valve agenesis (−/−; Itga9f/f; Tie2-Cre and Itga9f/f; Cdh5 (PAC)-CreERT2; Bazigou et al., 2009) | BECs and LECs (highest in valves), vascular SMCs |
| Fn1 (removal of EDA domain) | ECM component, ligand of Itg-α9 | Failure of lymphatic valve leaflet elongation (−/−; Bazigou et al., 2009) | Broad, including lymphatic valves |
| Emilin1 | Elastic microfibril-associated protein | Hyperplasia and abnormal patterning of lymphatic vessels, reduction of anchoring filaments; impaired lymph drainage, increased lymph leakage (−/−; Danussi et al., 2008) | Broad, including LECs |
| Other | |||
| Aspp1 | Cytoplasmic adaptor protein | Impaired assembly of lymphatic vessels and collecting lymphatic vessel patterning, accumulation of « lymphatic islands » (−/−; Hirashima et al., 2008) | Endothelial cells |
| Efnb2 (mutation of PDZ binding site) | Ligand of EphB receptor tyrosine kinases | Impaired sprouting of capillaries, agenesis of lymphatic valves, ectopic mural cells, chylothorax, retrograde lymph flow (−/−; Mäkinen et al., 2005) | Arterial endothelial cells and SMCs, LECs (highest in the valves) |
| Foxc2 | Transcription factor | Impaired patterning of capillaries, no collecting lymphatic vessels, agenesis of lymphatic valves, ectopic mural cells, retrograde lymph flow (−/−; Dagenais et al., 2004; Petrova et al., 2004; Norrmén et al., 2009) | Arterial endothelial cells and SMCs, LECs (highest in the valves) |
| Elk3 (Net) | Transcription factor | Lymphangiectasia, chylothorax (−/−; Ayadi et al., 2001) | Endothelial cells |
| PU.1 Csfr1 | Transcription factor receptor for M-CSF1 | Hyperplasia and abnormal patterning of dermal lymphatic vessels (−/−; Gordon et al., 2010) | Hematopoietic cells (stage dependent) |
ENU, N-ethyl-N-nitrosourea; PAC, P1-derived artificial chromosome.