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Class 3 semaphorins negatively regulate dermal lymphatic network formation.

Uchida Y, James JM, Suto F, Mukouyama YS - Biol Open (2015)

Bottom Line: In contrast, Sema3f;Sema3g double mutants display increased lymphatic branching, while Nrp2 mutants exhibit reduced lymphatic branching.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

No MeSH data available.


Related in: MedlinePlus

Normal lymphatic valve formation in Sema3f;Sema3g double mutants. Whole-mount staining of adult ear skin Sema3f−/−;Sema3glacZ/lacZ double mutants (A,A′) and WT controls (B,B′) with antibodies to the lymphatic valve marker α9-integrin (red) together with LYVE1 (green) and an pan-endothelial cells marker PECAM1 (blue). Arrowheads indicate lymphatic valves. A′ and B′ show only red and blue channels of A and B, respectively. Scale bar: 100 µm.
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BIO012302F8: Normal lymphatic valve formation in Sema3f;Sema3g double mutants. Whole-mount staining of adult ear skin Sema3f−/−;Sema3glacZ/lacZ double mutants (A,A′) and WT controls (B,B′) with antibodies to the lymphatic valve marker α9-integrin (red) together with LYVE1 (green) and an pan-endothelial cells marker PECAM1 (blue). Arrowheads indicate lymphatic valves. A′ and B′ show only red and blue channels of A and B, respectively. Scale bar: 100 µm.

Mentions: Whether the SEMA3s-mediated negative regulation influences LEC progenitor at an earlier stage and lymphatic network maturation and maintenance in a later embryonic stage and adult remain to be determined. At E11.5, Prox1+ LEC progenitors bud from the anterior cardinal vein and migrate towards the superficial skin (Fig. 7A). No apparent defective LEC progenitor migration was observed in Sema3f−/−;Sema3glacZ/lacZ double mutants, given that Nrp2 mutants exhibit lymph sac-like tubes which remain relatively adjacent to the cardinal vein (Fig. 7B,C). Like the abovementioned lymphatic phenotypes in the limb skin, the back skin of Nrp2 mutants exhibited hyperplastic lymphatic vasculature at E15.5 (Fig. 7E) and continued to display defective lymphatic vasculature at E17.5 (Fig. 7I). The back skin of Sema3f−/−;Sema3glacZ/lacZ double mutants also exhibited hyper branching phenotype (Fig. 7F,I). Defective lymphatic network was found in E17.5 limb skin of Nrp2 mutants and Sema3f−/−;Sema3glacZ/lacZ double mutants (arrowhead in Fig. 7K,L). Consistent with the previous study (Yuan et al., 2002), however, the defective lymphatic network appears to be recovered from E17.5 onwards. Furthermore, no apparent defective lymphatic network and valve formation was detectable in the adult ear skin (Fig. 7N,M; Fig. 8A,B). These data suggest that the recovery of lymphatic vessel development occurred during later embryonic stages and postnatal life in the mutants.Fig. 7.


Class 3 semaphorins negatively regulate dermal lymphatic network formation.

Uchida Y, James JM, Suto F, Mukouyama YS - Biol Open (2015)

Normal lymphatic valve formation in Sema3f;Sema3g double mutants. Whole-mount staining of adult ear skin Sema3f−/−;Sema3glacZ/lacZ double mutants (A,A′) and WT controls (B,B′) with antibodies to the lymphatic valve marker α9-integrin (red) together with LYVE1 (green) and an pan-endothelial cells marker PECAM1 (blue). Arrowheads indicate lymphatic valves. A′ and B′ show only red and blue channels of A and B, respectively. Scale bar: 100 µm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4582121&req=5

BIO012302F8: Normal lymphatic valve formation in Sema3f;Sema3g double mutants. Whole-mount staining of adult ear skin Sema3f−/−;Sema3glacZ/lacZ double mutants (A,A′) and WT controls (B,B′) with antibodies to the lymphatic valve marker α9-integrin (red) together with LYVE1 (green) and an pan-endothelial cells marker PECAM1 (blue). Arrowheads indicate lymphatic valves. A′ and B′ show only red and blue channels of A and B, respectively. Scale bar: 100 µm.
Mentions: Whether the SEMA3s-mediated negative regulation influences LEC progenitor at an earlier stage and lymphatic network maturation and maintenance in a later embryonic stage and adult remain to be determined. At E11.5, Prox1+ LEC progenitors bud from the anterior cardinal vein and migrate towards the superficial skin (Fig. 7A). No apparent defective LEC progenitor migration was observed in Sema3f−/−;Sema3glacZ/lacZ double mutants, given that Nrp2 mutants exhibit lymph sac-like tubes which remain relatively adjacent to the cardinal vein (Fig. 7B,C). Like the abovementioned lymphatic phenotypes in the limb skin, the back skin of Nrp2 mutants exhibited hyperplastic lymphatic vasculature at E15.5 (Fig. 7E) and continued to display defective lymphatic vasculature at E17.5 (Fig. 7I). The back skin of Sema3f−/−;Sema3glacZ/lacZ double mutants also exhibited hyper branching phenotype (Fig. 7F,I). Defective lymphatic network was found in E17.5 limb skin of Nrp2 mutants and Sema3f−/−;Sema3glacZ/lacZ double mutants (arrowhead in Fig. 7K,L). Consistent with the previous study (Yuan et al., 2002), however, the defective lymphatic network appears to be recovered from E17.5 onwards. Furthermore, no apparent defective lymphatic network and valve formation was detectable in the adult ear skin (Fig. 7N,M; Fig. 8A,B). These data suggest that the recovery of lymphatic vessel development occurred during later embryonic stages and postnatal life in the mutants.Fig. 7.

Bottom Line: In contrast, Sema3f;Sema3g double mutants display increased lymphatic branching, while Nrp2 mutants exhibit reduced lymphatic branching.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

No MeSH data available.


Related in: MedlinePlus