Abstract
JUNB, a subunit of the AP-1 transcription factor complex, mediates gene regulation in response to a plethora of extracellular stimuli. Previously, JUNB was shown to act as a critical positive regulator of blood vessel development and homeostasis as well as a negative regulator of proliferation, inflammation and tumour growth. Here, we demonstrate that the oncogenic miR-182 is a novel JUNB target. Loss-of-function studies by morpholino-mediated knockdown and the CRISPR/Cas9 technology identify a novel function for both JUNB and its target miR-182 in lymphatic vascular development in zebrafish. Furthermore, we show that miR-182 attenuates foxo1 expression indicating that strictly balanced Foxo1 levels are required for proper lymphatic vascular development in zebrafish. In conclusion, our findings uncover with the Junb/miR-182/Foxo1 regulatory axis a novel key player in governing lymphatic vascular morphogenesis in zebrafish.
Highlights
JUNB, a subunit of the AP-1 transcription factor complex, mediates gene regulation in response to a plethora of extracellular stimuli
Subsequent work revealed that the function of JUNB in these processes is mediated by transcriptional activation of its targets Vegfa[5], Cbfβ and Mmp[134] that act as important regulators of angiogenesis upon cellular hypoxia
Expression analyses in primary vascular smooth muscle cells and primary endothelial cells (ECs) derived from control or conditional Junb knockout mice (JunbΔ/− Col1α 2-cre)[24] confirmed that JUNB is essential for the full expression of the miR-183~96~182 cluster in vSMCs (Fig. 1d) and in ECs, albeit expression levels in ECs are rather low
Summary
JUNB, a subunit of the AP-1 transcription factor complex, mediates gene regulation in response to a plethora of extracellular stimuli. Loss-of-function studies by morpholino-mediated knockdown and the CRISPR/Cas[9] technology identify a novel function for both JUNB and its target miR-182 in lymphatic vascular development in zebrafish. We show that miR-182 attenuates foxo[1] expression indicating that strictly balanced Foxo[1] levels are required for proper lymphatic vascular development in zebrafish. Subsequent work revealed that the function of JUNB in these processes is mediated by transcriptional activation of its targets Vegfa[5], Cbfβ and Mmp[134] that act as important regulators of angiogenesis upon cellular hypoxia. We identify JUNB and a novel JUNB-dependent microRNA, miR-182, as essential regulators for proper lymphatic vascular development in zebrafish
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