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Background  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.    Methods  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.    Results  RNA-seq analyses in ACDMPV neonates revealed changes in the expression of several genes, including semaphorins ( SEMA s), neuropilin 1 ( NRP1 ), and plexins ( PLXN s), 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.    Conclusions  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.    Supplementary Information  The online version contains supplementary material available at 10.1186/s12931-021-01797-7.

Perturbation of semaphorin and VEGF signaling in ACDMPV lungs due to FOXF1 deficiency