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| Key factors |
Defects in lymphatic vascular system |
| Human syndrome | Mutant animals |
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| Transcription factors | | |
| SOX18 | Dominant-negative mutations of SOX18 have been linked with hypotrichosis-lymphedema-telangiectasia syndrome (OMIM no. 607823) [9]. | Sox18-null mice are devoid of lymphatic vessels and die in utero at 14.5 dpc from a generalized oedema [10]. |
| COUP-TFII | | Conditional inactivation of COUP-TFII during embryogenesis causes edema, haemorrhage, and blood-filled lymphatics [11]. |
| PROX-1 | | (i) Prox1−/− is embryonic lethality at approximately 14.5 dpc due to lack of lymphatic vasculature [12].
(ii) Conditional loss of Prox1 function in the adult has been shown to induce LECs to revert to a blood vascular phenotype [13]. |
| TBX1 | TBX1 mutation causes DiGeorge human syndrome, which is associated with multiple congenital anomalies. | Mouse embryos with conditional deletion of Tbx1 in endothelial cells display widespread lymphangiogenesis defects and have perinatal death [14]. |
| NFATc-1 | | (i) NFATc1-deficient mice showed irregular patterning of the LEC sprouting from the jugular lymph sac [15].
(ii) NFATc-1 and FOXC2 are downstream of VEGFR-3, cooperate in regulating the differentiation of lymphatic capillaries and valves formation [16]. |
| FOXC2 | Mutation in transcription factor FOXC2 caused lymphedema-distichiasis (LD) in human (OMIM no. 153400). | Foxc2−/− mice have abnormal lymphatic vascular patterning, increased pericyte investment of lymphatic vessels, and loss of valves in the collecting vessels [17]. |
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| Growth factors | |
| VEGF-C | | (i) The disruption of VEGF-C in mice, Xenopus tadpoles, and zebrafish leads to a defect in migration of early lymphatic endothelial cells away from cardinal veins to form lymphatic plexus [18–20].
(ii) Vegfc−/− mouse embryos completely lack lymphatic vasculature [18].
(iii) Vegfc−/−; Vegfd−/− double knockout fails to recapitulate the early embryonic lethality observed in Vegfr3−/− mice [21]. |
| VEGF-D | | VEGF-D deficiency mice displayed no lymphatic vessel dysfunction, suggesting that VEGF-D is dispensable and might not play a major role in lymphatic development [22]. |
| Angiopoietin-2 | | Ang2-mutant mice display an abnormal lymphatic network due to defective recruitment of smooth muscle cells to the lymphatic collecting vasculature [23]. |
| Adrenomedullin | | AM-, calcrl-, RAMP2-null mice died midgestation with formation of interstitial lymphedema. Loss of AM signalling caused abnormal jugular lymphatic vessels due to reduced LEC proliferation [24]. |
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| Receptors/transmembrane proteins | |
| VEGFR-3 | Heterozygous tyrosine kinase-inactivating missense point mutations of VEGFR-3 gene have been identified as a major cause of the Milroy disease (OMIM no. 153100). | Vegfr3 knockout mice display cardiovascular defects, severe blood vessel defects, and embryonic death [25]. |
| Integrin α9β1 | | (i) Integrin-α9β1-deficient mice die after birth due to chylothorax, an accumulation of lymph in pleural cavity [26].
(ii) Integrin-α9-deficient mice further were described as having abnormal lymphatic valves and impaired fluid transport [27]. |
| LYVE-1 | | (i) Mice lacking this receptor have normal lymphatic vessels.
(ii) LYVE-1 is expressed at the site where lymphangiogenesis will occur in the cardinal vein around 8.5 dpc [3]. |
| Podoplanin | | Podoplanin−/− mice died at birth and have lymphatic defects, associated with decreased lymphatic transport, lymphedema and dilation of lymphatic vessels [28]. |
| Neuropilin-2 | | Nrp2−/− mice show absence or severe reduction of small lymphatic vessels and capillaries during development, while arteries, veins, and collecting lymphatics developed normally [29]. |
| Ephrin-B2 | | Mice expressing a mutated form of Ephrin-B2 have major lymphatic defects, including disturbed postnatal lymphatic remodeling, hyperplasia, and lack of luminal valve formation, whereas the blood vasculature remained normal [30]. |
| Clp24, Claudin-like protein of 24 kDa | | (i) Clp24 knockdown in Danio rerio and Xenopus laevis display defective lymphatic development.
(ii) Clp24-/- mice have enlarged lymphatic vessels with abnormal patterning and smooth muscle cell recruitment [31]. |
| Liprin β1 | | Knock-down liprin β1 in Xenopus laevis tadpoles using morpholino leads to edema, defective assembly of lymphatic vessels [32]. |
| Synectin | | Knockdown of synectin in zebrafish causes impaired formation of the thoracic duct and defective lymphangiogenic sprouting [33]. |
| ALK1, activin receptor-like kinase 1 | | (i) ALK1 is a member of TGF-β type I family of receptors.
(ii) Blockade of ALK1 signalling using ALK1Fc results in failed remodelling of lymphatic vascular in neonatal mice [34]. |
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| Others | |
| SYK and SLP-76 | | Loss of SYK or SLP-76 function results in embryonic hemorrhage, arteriovenous shunting, blood-lymphatic connections, and blood-filled lymphatics [35]. |
| CCBE1 | Mutation in CCBE1 associates with the Hennekam syndrome, a generalised lymphatic dysplasia in humans [36]. | CCBE1 has been identified as essential factor for embryonic lymphangiogenesis and venous sprouting in zebrafish model [37]. |
| Aspp1, apoptosis-stimulating protein of p53 | | Aspp1−/− mice have embryonic subcutaneous edema, delayed lymphatic vessel formation, defective lymphatic drainage function and mispatterned collecting lymphatic vessels [38]. |
| Emilin-1 | | Emilin1−/− mice result in hyperplasia, enlargement, irregular pattern of lymphatic vessels with a reduction of anchoring filaments [39]. |
| miR-31, microRNA-targeting PROX1 | | Gain of miR-31 function leads to impaired venous sprouting and lymphatic vascular development in Xenopus and zebrafish; miR-31 is identified as negative regulator of lymphatic development [40]. |
| Rac1, Rho family GTPase | | Deletion of endothelial Rac1 in mice causes impaired lymphatic-blood vessel separation, identified by edema, haemorrhage, and embryonic lethality, whereas blood vessels remain normal [41]. |
| Spred-1/2 | | Spred-1/2 -deficient embryos display subcutaneous haemorrhage, edema, dilated and blood-filled lymphatic vessels and die in utero [42]. |
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