HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development

Gauvrit, Sébastien; Villasenor, Alethia; Strilić, Boris; Kitchen, Philip; Collins, Michelle M.; Marín-Juez, Rubén; Guenther, Stefan; Maischein, Hans-Martin; Fukuda, Naoto; Canham, Maurice A.; Brickman, Joshua M.; Bogue, Clifford W.; Jayaraman, Padma-Sheela; Stainier, Didier Y. R.

doi:10.1038/s41467-018-05039-1

Cited by 74 publications

(70 citation statements)

References 70 publications

(84 reference statements)

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“…Mammalian TgfbrI / Alk5 has two paralogs in zebrafish, alk5a and alk5b , and from multiple datasets (Pauli et al, 2012; Yang et al, 2013; Gauvrit et al, 2018; Mullapudi et al, 2018), we found alk5b to be the highest expressed paralog during embryogenesis. To investigate its expression, we performed in situ hybridization and generated a transgenic reporter line, TgBAC ( alk5b:eGFP ), by bacterial artificial chromosome (BAC) recombineering (Figure S1).…”

Section: Resultsmentioning

confidence: 69%

Endothelial TGF-β signaling instructs smooth muscle development in the cardiac outflow tract

Boezio

Bensimon-Brito

Piesker

et al. 2020

Preprint

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19The development of the cardiac outflow tract (OFT), which connects the heart to the great 20 arteries, relies on a complex crosstalk between endothelial (ECs) and smooth muscle (SMCs) 21 cells. Defects in OFT development can lead to severe malformations, including aortic 22 aneurysms, which have often been associated with impaired TGF-β signaling. To further 23 investigate the role of TGF-β signaling in OFT formation, we generated zebrafish lacking the 24 type I TGF-β receptor Alk5 and found a strikingly specific dilation of the OFT. alk5 mutants 25 also exhibit increased EC numbers, extracellular matrix (ECM) and SMC disorganization. 26 Surprisingly, endothelial-specific alk5 overexpression in alk5 mutants rescues both 27 endothelial and SMC defects. Furthermore, modulation of the ECM gene fibulin-5, a TGF-β 28 target, partially restores OFT morphology and function. These findings reveal a new 29 requirement for endothelial TGF-β signaling in OFT morphogenesis and suggest an important 30 role for the endothelium in the etiology of aortic malformations.31 32

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Section: Resultsmentioning

confidence: 69%

Endothelial TGF-β signaling instructs smooth muscle development in the cardiac outflow tract

Boezio

Bensimon-Brito

Piesker

et al. 2020

Preprint

Self Cite

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“…See Supplementary Table 9 for list of top 25 conserved marker genes. 48 TLS and embryo data were integrated as described above. For the analysis, the in vivo cell states were used as a reference, and compared to the TLS cells attributed to that cluster.…”

Section: Analysis Of Conserved Marker Genesmentioning

confidence: 99%

Mouse embryonic stem cells self-organize into trunk-like structures with neural tube and somites

Veenvliet

Bolondi

Kretzmer

et al. 2020

Preprint

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One sentence summary: A platform for generating trunk-like-structures with precursors of spinal cord, bone and muscle from stem cells in a dish Abstract: Post-implantation embryogenesis is a highly dynamic process comprising multiple lineage decisions and morphogenetic changes inaccessible to deep analysis in vivo. Mouse embryonic stem cells (mESCs) can form aggregates reflecting the post-occipital embryo (gastruloids), but lacking proper morphogenesis. Here we show that embedding of aggregates derived from mESCs in an extracellular matrix compound results in Trunk-Like-Structures (TLS) with a high level of organization comprising a neural tube and somites. Comparative single-cell RNA-seq analysis demonstrates that TLS execute gene-regulatory programs in an embryo-like order, and generate primordial germ cell like cells (PGCLCs). TLS lacking Tbx6 form ectopic neural tubes, mirroring the embryonic mutant phenotype. ESC-derived trunk-like structures thus constitute a novel powerful in vitro platform for investigating lineage decisions and morphogenetic processes shaping the post-implantation embryo.2 Vertebrate post-implantation development comprises a multitude of complex morphogenetic 1 processes, which result from self-organization of stem cells and their descendants shaping the 2 embryonic body plan 1 . Recently developed stem cell models represent powerful platforms for 3 deconstructing the dynamics of these processes that are inaccessible in the embryo 1, 2 . The 4 most advanced models in terms of developmental stage accomplished so far are gastruloids 2,3 , 5 aggregates of mESCs able to self-organize into the three body axes 3 . However, gastruloids lack 6 proper morphogenesis, such as a failure of neural tube formation from neural cells or somite 7 condensation from presomitic cells 3 . In vivo, the extracellular matrix (ECM) has a critical role in 8 tissue morphogenesis 4 . In vitro, matrigel can serve as ECM surrogate, and culture media 9 supplemented with a low percentage of matrigel have been shown to induce complex 10 morphogenesis in organoids 5 . 11We therefore explored if embryo-like morphogenetic features could be induced by 12 embedding 96h post aggregation gastruloids in 5% matrigel for an additional 24h period ( Fig. 13 1a). We also tested a combination of matrigel together with the WNT signaling activator 14 CHIR99021 (CHIR) and the BMP signaling inhibitor LDN193189 (LDN), that have been reported 15 to induce a (pre-)somitic mesoderm ((P)SM) fate in 2D and 3D differentiation protocols 6-8 . To 16 facilitate high-throughput characterization and quantification of our conditions, we generated 17 mESCs with T::H2B-mCherry (hereafter T mCH ) and Sox2::H2B-Venus (hereafter Sox2 VE ) reporters, 18 marking the mesodermal (ME) or neural (NE) lineage respectively (Extended Data Fig. 1a). 19 Strikingly, embedding in 5% matrigel alone was sufficient for segmentation in the T mCH+ ME 20 domain and formation of a Sox2 VE+ neural tube like structure ( Fig. 1b,d; Extended Data Fig. 21 1b,c). The vast majorit...

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“…In adults, inflammation induces robust up-regulation of VEGFC expression by macrophages (Baluk et al, 2005). In addition, various hormones, transcription factors, metallothioneins, and microenvironmental stresses (e.g., hyperthermia, oxidative stress, and high salt) were shown to control VEGFC expression (Cohen et al, 2009;Machnik et al, 2009;Sapoznik et al, 2009;Chen et al, 2012;Schuermann et al, 2015;Gauvrit et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

BACH family members regulate angiogenesis and lymphangiogenesis by modulating VEGFC expression

Cohen¹,

Tempelhof²,

Raz

et al. 2020

Life Sci. Alliance

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Angiogenesis and lymphangiogenesis are key processes during embryogenesis as well as under physiological and pathological conditions. Vascular endothelial growth factor C (VEGFC), the ligand for both VEGFR2 and VEGFR3, is a central lymphangiogenic regulator that also drives angiogenesis. Here, we report that members of the highly conserved BACH (BTB and CNC homology) family of transcription factors regulate VEGFC expression, through direct binding to its promoter. Accordingly, down-regulation of bach2a hinders blood vessel formation and impairs lymphatic sprouting in a Vegfc-dependent manner during zebrafish embryonic development. In contrast, BACH1 overexpression enhances intratumoral blood vessel density and peritumoral lymphatic vessel diameter in ovarian and lung mouse tumor models. The effects on the vascular compartment correlate spatially and temporally with BACH1 transcriptional regulation of VEGFC expression. Altogether, our results uncover a novel role for the BACH/VEGFC signaling axis in lymphatic formation during embryogenesis and cancer, providing a novel potential target for therapeutic interventions.

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HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development

Cited by 74 publications

References 70 publications

Endothelial TGF-β signaling instructs smooth muscle development in the cardiac outflow tract

Endothelial TGF-β signaling instructs smooth muscle development in the cardiac outflow tract

Mouse embryonic stem cells self-organize into trunk-like structures with neural tube and somites

BACH family members regulate angiogenesis and lymphangiogenesis by modulating VEGFC expression

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