PMID- 31852686 OWN - NLM STAT- MEDLINE DCOM- 20200702 LR - 20200702 IS - 1477-9129 (Electronic) IS - 0950-1991 (Linking) VI - 147 IP - 2 DP - 2020 Jan 17 TI - FOXO1 regulates developmental lymphangiogenesis by upregulating CXCR4 in the mouse-tail dermis. LID - dev181545 [pii] LID - 10.1242/dev.181545 [doi] AB - Lymphangiogenesis plays important roles in normal fetal development and postnatal growth. However, its molecular regulation remains unclear. Here, we have examined the function of forkhead box protein O1 (FOXO1) transcription factor, a known angiogenic factor, in developmental dermal lymphangiogenesis using endothelial cell-specific FOXO1-deficient mice. FOXO1-deficient mice showed disconnected and dilated lymphatic vessels accompanied with increased proliferation and decreased apoptosis in the lymphatic capillaries. Comprehensive DNA microarray analysis of the causes of in vivo phenotypes in FOXO1-deficient mice revealed that the gene encoding C-X-C chemokine receptor 4 (CXCR4) was the most drastically downregulated in FOXO1-deficient primary lymphatic endothelial cells (LECs). CXCR4 was expressed in developing dermal lymphatic capillaries in wild-type mice but not in FOXO1-deficient dermal lymphatic capillaries. Furthermore, FOXO1 suppression impaired migration toward the exogenous CXCR4 ligand, C-X-C chemokine ligand 12 (CXCL12), and coordinated proliferation in LECs. These results suggest that FOXO1 serves an essential role in normal developmental lymphangiogenesis by promoting LEC migration toward CXCL12 and by regulating their proliferative activity. This study provides valuable insights into the molecular mechanisms underlying developmental lymphangiogenesis. CI - (c) 2020. Published by The Company of Biologists Ltd. FAU - Niimi, Kenta AU - Niimi K AD - Group of Neurobiology, Division of Health Science, Osaka University Graduate School of Medicine, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan. AD - Kagawa Prefectural University of Health Sciences, Hara 281-1, Mure, Takamatsu, Kagawa 761-0123, Japan. FAU - Kohara, Misaki AU - Kohara M AD - Group of Neurobiology, Division of Health Science, Osaka University Graduate School of Medicine, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan. FAU - Sedoh, Eriko AU - Sedoh E AD - Kagawa Prefectural University of Health Sciences, Hara 281-1, Mure, Takamatsu, Kagawa 761-0123, Japan. FAU - Fukumoto, Moe AU - Fukumoto M AD - Group of Neurobiology, Division of Health Science, Osaka University Graduate School of Medicine, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan. FAU - Shibata, Satoshi AU - Shibata S AD - Group of Neurobiology, Division of Health Science, Osaka University Graduate School of Medicine, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan. FAU - Sawano, Toshinori AU - Sawano T AD - Group of Neurobiology, Division of Health Science, Osaka University Graduate School of Medicine, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan. FAU - Tashiro, Fumi AU - Tashiro F AD - Department of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan. FAU - Miyazaki, Satsuki AU - Miyazaki S AD - Department of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan. FAU - Kubota, Yoshiaki AU - Kubota Y AD - Department of Anatomy, Keio University School of Medicine, 35-Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. FAU - Miyazaki, Jun-Ichi AU - Miyazaki JI AD - Department of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan. FAU - Inagaki, Shinobu AU - Inagaki S AUID- ORCID: 0000-0002-2785-1214 AD - Group of Neurobiology, Division of Health Science, Osaka University Graduate School of Medicine, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan inagaki@sahs.med.osaka-u.ac.jp furuyama@chs.pref.kagawa.jp. FAU - Furuyama, Tatsuo AU - Furuyama T AUID- ORCID: 0000-0001-7349-103X AD - Kagawa Prefectural University of Health Sciences, Hara 281-1, Mure, Takamatsu, Kagawa 761-0123, Japan inagaki@sahs.med.osaka-u.ac.jp furuyama@chs.pref.kagawa.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200117 PL - England TA - Development JT - Development (Cambridge, England) JID - 8701744 RN - 0 (Antigens, CD) RN - 0 (Cadherins) RN - 0 (Chemokine CXCL12) RN - 0 (Forkhead Box Protein O1) RN - 0 (Foxo1 protein, mouse) RN - 0 (Receptors, CXCR4) RN - 0 (cadherin 5) RN - EC 2.7.7.- (Cre recombinase) RN - EC 2.7.7.- (Integrases) SB - IM MH - Animals MH - Animals, Newborn MH - Antigens, CD/metabolism MH - Apoptosis MH - Base Sequence MH - Cadherins/metabolism MH - Cell Death MH - Cell Proliferation MH - Chemokine CXCL12/metabolism MH - Dermis/*metabolism MH - Endothelial Cells/cytology/metabolism MH - Enhancer Elements, Genetic/genetics MH - Forkhead Box Protein O1/*metabolism MH - Gene Deletion MH - *Gene Expression Regulation, Developmental MH - Integrases/metabolism MH - Lymphangiogenesis/*genetics MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Models, Biological MH - Promoter Regions, Genetic/genetics MH - Protein Binding MH - Receptors, CXCR4/*genetics/metabolism MH - Tail/*metabolism MH - Up-Regulation/*genetics OTO - NOTNLM OT - C-X-C chemokine ligand 12 (CXCL-12) OT - C-X-C chemokine receptor type 4 (CXCR-4) OT - Chemokine OT - FOXO OT - Lymphangiogenesis OT - Tail dermis COIS- Competing interestsThe authors declare no competing or financial interests. EDAT- 2019/12/20 06:00 MHDA- 2020/07/03 06:00 CRDT- 2019/12/20 06:00 PHST- 2019/06/14 00:00 [received] PHST- 2019/12/10 00:00 [accepted] PHST- 2019/12/20 06:00 [pubmed] PHST- 2020/07/03 06:00 [medline] PHST- 2019/12/20 06:00 [entrez] AID - dev.181545 [pii] AID - 10.1242/dev.181545 [doi] PST - epublish SO - Development. 2020 Jan 17;147(2):dev181545. doi: 10.1242/dev.181545.