The blood vasculature instructs lymphatic patterning in a SOX7-dependent manner.
The blood vasculature instructs lymphatic patterning in a SOX7-dependent manner.
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DOI：
10.15252/embj.2021109032
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发表时间：
2023-03-01
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尽管越来越多的目录分泌因子的淋巴网络组装的关键，很少有人知道的机制，调节这些分子线索在血管内皮细胞（BEC）的表达水平。在这里，我们发现BEC特异性转录因子SOX 7通过调节血管分泌信号的转录以形成淋巴管，在非细胞自主方式中起着至关重要的作用。虽然SOX 7在淋巴管内皮细胞（LEC）中不表达，但小鼠胚胎中SOX 7功能的条件性丧失导致畸形的真皮淋巴管表型。我们在小鼠和人类中鉴定了新的远距离调控区域，这些区域以SOX 7依赖性方式直接抑制主要淋巴管生成生长因子（Vegfc）的转录。此外，我们表明，SOX 7直接结合HEY 1，一个典型的抑制的Notch途径，这表明转录抑制也可以通过招募这种蛋白质伴侣在Vegfc基因组调控区调制。我们的工作揭示了SOX 7在调节下游信号传导事件中的作用，这些事件对淋巴图案化至关重要，至少部分地通过血管内皮中VEGFC水平的转录抑制。S0X7抑制血管内皮中淋巴管生成因子VEGFC的转录以维持淋巴管的适当模式。
Despite a growing catalog of secreted factors critical for lymphatic network assembly, little is known about the mechanisms that modulate the expression level of these molecular cues in blood vascular endothelial cells (BECs). Here, we show that a BEC‐specific transcription factor, SOX7, plays a crucial role in a non‐cell‐autonomous manner by modulating the transcription of angiocrine signals to pattern lymphatic vessels. While SOX7 is not expressed in lymphatic endothelial cells (LECs), the conditional loss of SOX7 function in mouse embryos causes a dysmorphic dermal lymphatic phenotype. We identify novel distant regulatory regions in mice and humans that contribute to directly repressing the transcription of a major lymphangiogenic growth factor (Vegfc) in a SOX7‐dependent manner. Further, we show that SOX7 directly binds HEY1, a canonical repressor of the Notch pathway, suggesting that transcriptional repression may also be modulated by the recruitment of this protein partner at Vegfc genomic regulatory regions. Our work unveils a role for SOX7 in modulating downstream signaling events crucial for lymphatic patterning, at least in part via the transcriptional repression of VEGFC levels in the blood vascular endothelium. SOX7 represses transcription of the lymphangiogenic factor VEGFC in the blood vascular endothelium to maintain proper patterning of lymphatic vessels.