Abstract
BackgroundAlveolar 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.MethodsTo 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.ResultsRNA-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.ConclusionsOur 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.
Highlights
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
Using comparative analyses and an over-representation approach, we have investigated deregulated pathways to elucidate potential crosstalk between FOXF1 and other genes required for normal lung development in humans
In our recent ChIP-seq study performed in IMR-90 fetal lung fibroblasts, we demonstrated that TBX2 and/ or TBX4 bind to FOXF1, FENDRR, their promoter(s) and lung-specific enhancer, as well as to genes from the axon guidance/SEMA signaling (SEMAs, PLXNs, and NRP), that were found to be deregulated in ACDMPV patients in this study
Summary
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. Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV, MIM #265380) is a rarely diagnosed lethal lung developmental disorder (LLDD) in neonates [1,2,3,4,5,6]. Histopathological findings in ACDMPV include reduced number of pulmonary capillaries, majority of which do not make contact with the alveolar epithelium, thickening of intra-alveolar septa and reduced alveolarization, medial hypertrophy of small peripheral pulmonary arteries and arterioles, and the presence of vascular anastomoses. Most patients with ACDMPV often manifest anomalies of the cardiovascular, gastrointestinal, and genitourinary systems [3,4,5, 16]
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