Atypical E2fs control lymphangiogenesis through transcriptional regulation of Ccbe1 and Flt4.
Lymphatic vessels are derived from venous endothelial cells and their formation is governed by the Vascular endothelial growth factor C (VegfC)/Vegf receptor 3 (Vegfr3; Flt4) signaling pathway. Recent studies show that Collagen and Calcium Binding EGF domains 1 protein (Ccbe1) enhances VegfC-depende...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3771987?pdf=render |
| _version_ | 1828473618533711872 |
|---|---|
| author | Bart G M W Weijts Andreas van Impel Stefan Schulte-Merker Alain de Bruin |
| author_facet | Bart G M W Weijts Andreas van Impel Stefan Schulte-Merker Alain de Bruin |
| author_sort | Bart G M W Weijts |
| collection | DOAJ |
| description | Lymphatic vessels are derived from venous endothelial cells and their formation is governed by the Vascular endothelial growth factor C (VegfC)/Vegf receptor 3 (Vegfr3; Flt4) signaling pathway. Recent studies show that Collagen and Calcium Binding EGF domains 1 protein (Ccbe1) enhances VegfC-dependent lymphangiogenesis. Both Ccbe1 and Flt4 have been shown to be indispensable for lymphangiogenesis. However, how these essential players are transcriptionally regulated remains poorly understood. In the case of angiogenesis, atypical E2fs (E2f7 and E2f8) however have been recently shown to function as transcriptional activators for VegfA. Using a genome-wide approach we here identified both CCBE1 and FLT4 as direct targets of atypical E2Fs. E2F7/8 directly bind and stimulate the CCBE1 promoter, while recruitment of E2F7/8 inhibits the FLT4 promoter. Importantly, inactivation of e2f7/8 in zebrafish impaired venous sprouting and lymphangiogenesis with reduced ccbe1 expression and increased flt4 expression. Remarkably, over-expression of e2f7/8 rescued Ccbe1- and Flt4-dependent lymphangiogenesis phenotypes. Together these results identified E2f7/8 as novel in vivo transcriptional regulators of Ccbe1 and Flt4, both essential genes for venous sprouting and lymphangiogenesis. |
| first_indexed | 2024-12-11T05:47:08Z |
| format | Article |
| id | doaj.art-ce80f8056e804827bd4a73d27ffb7ff0 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T05:47:08Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-ce80f8056e804827bd4a73d27ffb7ff02022-12-22T01:18:56ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0189e7369310.1371/journal.pone.0073693Atypical E2fs control lymphangiogenesis through transcriptional regulation of Ccbe1 and Flt4.Bart G M W WeijtsAndreas van ImpelStefan Schulte-MerkerAlain de BruinLymphatic vessels are derived from venous endothelial cells and their formation is governed by the Vascular endothelial growth factor C (VegfC)/Vegf receptor 3 (Vegfr3; Flt4) signaling pathway. Recent studies show that Collagen and Calcium Binding EGF domains 1 protein (Ccbe1) enhances VegfC-dependent lymphangiogenesis. Both Ccbe1 and Flt4 have been shown to be indispensable for lymphangiogenesis. However, how these essential players are transcriptionally regulated remains poorly understood. In the case of angiogenesis, atypical E2fs (E2f7 and E2f8) however have been recently shown to function as transcriptional activators for VegfA. Using a genome-wide approach we here identified both CCBE1 and FLT4 as direct targets of atypical E2Fs. E2F7/8 directly bind and stimulate the CCBE1 promoter, while recruitment of E2F7/8 inhibits the FLT4 promoter. Importantly, inactivation of e2f7/8 in zebrafish impaired venous sprouting and lymphangiogenesis with reduced ccbe1 expression and increased flt4 expression. Remarkably, over-expression of e2f7/8 rescued Ccbe1- and Flt4-dependent lymphangiogenesis phenotypes. Together these results identified E2f7/8 as novel in vivo transcriptional regulators of Ccbe1 and Flt4, both essential genes for venous sprouting and lymphangiogenesis.http://europepmc.org/articles/PMC3771987?pdf=render |
| spellingShingle | Bart G M W Weijts Andreas van Impel Stefan Schulte-Merker Alain de Bruin Atypical E2fs control lymphangiogenesis through transcriptional regulation of Ccbe1 and Flt4. PLoS ONE |
| title | Atypical E2fs control lymphangiogenesis through transcriptional regulation of Ccbe1 and Flt4. |
| title_full | Atypical E2fs control lymphangiogenesis through transcriptional regulation of Ccbe1 and Flt4. |
| title_fullStr | Atypical E2fs control lymphangiogenesis through transcriptional regulation of Ccbe1 and Flt4. |
| title_full_unstemmed | Atypical E2fs control lymphangiogenesis through transcriptional regulation of Ccbe1 and Flt4. |
| title_short | Atypical E2fs control lymphangiogenesis through transcriptional regulation of Ccbe1 and Flt4. |
| title_sort | atypical e2fs control lymphangiogenesis through transcriptional regulation of ccbe1 and flt4 |
| url | http://europepmc.org/articles/PMC3771987?pdf=render |
| work_keys_str_mv | AT bartgmwweijts atypicale2fscontrollymphangiogenesisthroughtranscriptionalregulationofccbe1andflt4 AT andreasvanimpel atypicale2fscontrollymphangiogenesisthroughtranscriptionalregulationofccbe1andflt4 AT stefanschultemerker atypicale2fscontrollymphangiogenesisthroughtranscriptionalregulationofccbe1andflt4 AT alaindebruin atypicale2fscontrollymphangiogenesisthroughtranscriptionalregulationofccbe1andflt4 |