Lung diseases are the leading causes of mortality, especially in infants and young children (Zar et al., 2014). Down syndrome (DS), which is caused by an extra copy of human chromosome 21 (Hsa21), is the most frequently occurring chromosomal disorder (Antonarakis et al., 2020). Impaired lung alveolar and vascular development has been reported in DS (Bush et al., 2017; Danopoulos et al., 2021). Individuals with DS have an increased frequency of respiratory tract infection, pulmonary hypertension and other lung-related diseases (Colvin and Yeager, 2017).

Hsa21 contains more than 200 protein-coding genes and multiple nonprotein-coding genes (Antonarakis et al., 2020). How the increased expression of these genes caused by trisomy 21 contributes to lung diseases in DS remains poorly understood. A better understanding of the etiology underlying lung diseases in DS may benefit not only persons with trisomy 21 but also the general population. Mouse models are valuable for genetic disease studies (Herault et al., 2017). The genes on Hsa21 are evolutionarily conserved to three regions on mouse chromosome 10 (Mmu10), Mmu16, and Mmu17. The DS mouse model Dp16 (Dp(16Lipi-Zfp295)1Yey) contains a segmental chromosomal duplication containing the entire Hsa21 syntenic region on Mmu16 (Li et al., 2007).

In this study, we utilized the Dp16 mouse model to explore the dosage effects of the corresponding genes on lung diseases. We showed here that the Dp16 mice presented impaired alveolar development with reduced alveoli and enlarged alveolar air spaces, hyperplasia of vascular smooth muscle cells, and transient pulmonary artery hypertension (PAH). A single-cell transcriptome atlas of the Dp16 lung cells was established to facilitate further exploring the key causative genes and intercellular communications underlying these DS-related lung diseases.