Class 3 semaphorins negatively regulate dermal lymphatic network formation
The development of a patterned lymphatic vascular network is essential for proper lymphatic functions during organ development and homeostasis. Here we report that class 3 semaphorins (SEMA3s), SEMA3F and SEMA3G negatively regulate lymphatic endothelial cell (LEC) growth and sprouting to control der...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2015-09-01
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| Series: | Biology Open |
| Subjects: | |
| Online Access: | http://bio.biologists.org/content/4/9/1194 |
| _version_ | 1818922923738529792 |
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| author | Yutaka Uchida Jennifer M. James Fumikazu Suto Yoh-suke Mukouyama |
| author_facet | Yutaka Uchida Jennifer M. James Fumikazu Suto Yoh-suke Mukouyama |
| author_sort | Yutaka Uchida |
| collection | DOAJ |
| description | The development of a patterned lymphatic vascular network is essential for proper lymphatic functions during organ development and homeostasis. Here we report that class 3 semaphorins (SEMA3s), SEMA3F and SEMA3G negatively regulate lymphatic endothelial cell (LEC) growth and sprouting to control dermal lymphatic network formation. Neuropilin2 (NRP2) functions as a receptor for SEMA3F and SEMA3G, as well as vascular endothelial growth factor C (VEGFC). In culture, Both SEMA3F and SEMA3G inhibit VEGFC-mediated sprouting and proliferation of human dermal LECs. In the developing mouse skin, Sema3f is expressed in the epidermis and Sema3g expression is restricted to arteries, whereas their receptor Nrp2 is preferentially expressed by lymphatic vessels. Both Sema3f;Sema3g double mutants and Nrp2 mutants exhibit increased LEC growth in the skin. In contrast, Sema3f;Sema3g double mutants display increased lymphatic branching, while Nrp2 mutants exhibit reduced lymphatic branching. A targeted mutation in PlexinA1 or PlexinA2, signal transducers forming a receptor complex with NRP2 for SEMA3s, exhibits an increase in LEC growth and lymphatic branching as observed in Sema3f;Sema3g double mutants. Our results provide the first evidence that SEMA3F and SEMA3G function as a negative regulator for dermal lymphangiogenesis in vivo. The reciprocal phenotype in lymphatic branching between Sema3f;Sema3g double mutants and Nrp2 mutants suggest a complex NRP2 function that regulates LEC behavior both positively and negatively, through a binding with VEGFC or SEMA3s. |
| first_indexed | 2024-12-20T02:01:15Z |
| format | Article |
| id | doaj.art-5f4e838de142494f8036721a0ea49794 |
| institution | Directory Open Access Journal |
| issn | 2046-6390 |
| language | English |
| last_indexed | 2024-12-20T02:01:15Z |
| publishDate | 2015-09-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Biology Open |
| spelling | doaj.art-5f4e838de142494f8036721a0ea497942022-12-21T19:57:18ZengThe Company of BiologistsBiology Open2046-63902015-09-01491194120510.1242/bio.012302012302Class 3 semaphorins negatively regulate dermal lymphatic network formationYutaka Uchida0Jennifer M. James1Fumikazu Suto2Yoh-suke Mukouyama3 Laboratory of Stem Cell and Neuro-Vascular Biology, Genetics and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10/6C103, 10 Center Drive, Bethesda, MD 20892, USA Laboratory of Stem Cell and Neuro-Vascular Biology, Genetics and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10/6C103, 10 Center Drive, Bethesda, MD 20892, USA Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan Laboratory of Stem Cell and Neuro-Vascular Biology, Genetics and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10/6C103, 10 Center Drive, Bethesda, MD 20892, USA The development of a patterned lymphatic vascular network is essential for proper lymphatic functions during organ development and homeostasis. Here we report that class 3 semaphorins (SEMA3s), SEMA3F and SEMA3G negatively regulate lymphatic endothelial cell (LEC) growth and sprouting to control dermal lymphatic network formation. Neuropilin2 (NRP2) functions as a receptor for SEMA3F and SEMA3G, as well as vascular endothelial growth factor C (VEGFC). In culture, Both SEMA3F and SEMA3G inhibit VEGFC-mediated sprouting and proliferation of human dermal LECs. In the developing mouse skin, Sema3f is expressed in the epidermis and Sema3g expression is restricted to arteries, whereas their receptor Nrp2 is preferentially expressed by lymphatic vessels. Both Sema3f;Sema3g double mutants and Nrp2 mutants exhibit increased LEC growth in the skin. In contrast, Sema3f;Sema3g double mutants display increased lymphatic branching, while Nrp2 mutants exhibit reduced lymphatic branching. A targeted mutation in PlexinA1 or PlexinA2, signal transducers forming a receptor complex with NRP2 for SEMA3s, exhibits an increase in LEC growth and lymphatic branching as observed in Sema3f;Sema3g double mutants. Our results provide the first evidence that SEMA3F and SEMA3G function as a negative regulator for dermal lymphangiogenesis in vivo. The reciprocal phenotype in lymphatic branching between Sema3f;Sema3g double mutants and Nrp2 mutants suggest a complex NRP2 function that regulates LEC behavior both positively and negatively, through a binding with VEGFC or SEMA3s.http://bio.biologists.org/content/4/9/1194SEMA3sNRP2Dermal lymphangiogenesisLEC sproutingLEC growth |
| spellingShingle | Yutaka Uchida Jennifer M. James Fumikazu Suto Yoh-suke Mukouyama Class 3 semaphorins negatively regulate dermal lymphatic network formation Biology Open SEMA3s NRP2 Dermal lymphangiogenesis LEC sprouting LEC growth |
| title | Class 3 semaphorins negatively regulate dermal lymphatic network formation |
| title_full | Class 3 semaphorins negatively regulate dermal lymphatic network formation |
| title_fullStr | Class 3 semaphorins negatively regulate dermal lymphatic network formation |
| title_full_unstemmed | Class 3 semaphorins negatively regulate dermal lymphatic network formation |
| title_short | Class 3 semaphorins negatively regulate dermal lymphatic network formation |
| title_sort | class 3 semaphorins negatively regulate dermal lymphatic network formation |
| topic | SEMA3s NRP2 Dermal lymphangiogenesis LEC sprouting LEC growth |
| url | http://bio.biologists.org/content/4/9/1194 |
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