Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare lethal congenital lung disorder in neonates characterized by severe progressive respiratory failure and refractory pulmonary hypertension, resulting from underdevelopment of the peripheral pulmonary tree. Causative heterozygous single nucleotide variants (SNVs) or copy-number variant (CNV) deletions involving FOXF1 or its distant lung-specific enhancer on chromosome 16q24.1 have been identified in 80–90% of ACDMPV patients. FOXF1 maps closely to and regulates the oppositely oriented FENDRR, with which it also shares regulatory elements. To better understand the transcriptional networks downstream of FOXF1 that are relevant for lung organogenesis, using RNA-seq, we have examined lung transcriptomes in 12 histopathologically verified ACDMPV patients with or without pathogenic variants in the FOXF1 locus and analyzed gene expression profile in FENDRR-depleted fetal lung fibroblasts, IMR-90. RNA-seq analyses in ACDMPV neonates revealed changes in the expression of several genes, including semaphorins (SEMAs), neuropilin 1 (NRP1), and plexins (PLXNs), essential for both epithelial branching and vascular patterning. In addition, we have found deregulation of the vascular endothelial growth factor (VEGF) signaling that also controls pulmonary vasculogenesis and a lung-specific endothelial gene TMEM100 known to be essential in vascular morphogenesis. Interestingly, we have observed a substantial difference in gene expression profiles between the ACDMPV samples with different types of FOXF1 defect. Moreover, partial overlap between transcriptome profiles of ACDMPV lungs with FOXF1 SNVs and FENDRR-depleted IMR-90 cells suggests contribution of FENDRR to ACDMPV etiology. Our transcriptomic data imply potential crosstalk between several lung developmental pathways, including interactions between FOXF1-SHH and SEMA-NRP or VEGF/VEGFR2 signaling, and provide further insight into complexity of lung organogenesis in humans.

中文翻译：

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由于 FOXF1 缺乏导致 ACDMPV 肺中信号素和 VEGF 信号的扰动

肺泡毛细血管发育不良伴肺静脉错位 (ACDMPV) 是一种罕见的致命性先天性新生儿肺部疾病，其特征是严重的进行性呼吸衰竭和顽固性肺动脉高压，由外周肺树发育不全所致。在 80-90% 的 ACDMPV 患者中发现了致病性杂合单核苷酸变异 (SNV) 或拷贝数变异 (CNV) 缺失，涉及 FOXF1 或其在染色体 16q24.1 上的远处肺特异性增强子。FOXF1 密切映射并调节相反方向的 FENDRR，它还与 FENDRR 共享调节元素。为了更好地了解 FOXF1 下游与肺器官发生相关的转录网络，使用 RNA-seq，我们检查了 12 名经组织病理学证实的 ACDMPV 患者的肺转录组，在 FOXF1 基因座中有或没有致病性变异，并分析了 FENDRR 耗尽的胎儿肺成纤维细胞 IMR-90 中的基因表达谱。ACDMPV 新生儿的 RNA-seq 分析揭示了几种基因表达的变化，包括信号蛋白 (SEMA)、神经纤毛蛋白 1 (NRP1) 和丛蛋白 (PLXN)，这些基因对上皮分支和血管图案形成都至关重要。此外，我们发现血管内皮生长因子 (VEGF) 信号传导的失调也控制肺血管生成和已知在血管形态发生中必不可少的肺特异性内皮基因 TMEM100。有趣的是，我们观察到具有不同类型 FOXF1 缺陷的 ACDMPV 样本之间的基因表达谱存在显着差异。而且，ACDMPV 肺的转录组谱与 FOXF1 SNV 和 FENDRR 耗尽的 IMR-90 细胞之间的部分重叠表明 FENDRR 对 ACDMPV 病因的贡献。我们的转录组数据暗示了几种肺发育途径之间的潜在串扰，包括 FOXF1-SHH 和 SEMA-NRP 或 VEGF/VEGFR2 信号之间的相互作用，并提供了对人类肺器官发生复杂性的进一步了解。