Abstract
Lung development occurs under relative hypoxia and the most important oxygen-sensitive response pathway is driven by Hypoxia Inducible Factors (HIF). HIFs are heterodimeric transcription factors of an oxygen-sensitive subunit, HIFα, and a constitutively expressed subunit, HIF1β. HIF1α and HIF2α, encoded by two separate genes, contribute to the activation of hypoxia inducible genes. A third HIFα gene, HIF3α, is subject to alternative promoter usage and splicing, leading to three major isoforms, HIF3α, NEPAS and IPAS. HIF3α gene products add to the complexity of the hypoxia response as they function as dominant negative inhibitors (IPAS) or weak transcriptional activators (HIF3α/NEPAS). Previously, we and others have shown the importance of the Hif1α and Hif2α factors in lung development, and here we investigated the role of Hif3α during pulmonary development. Therefore, HIF3α was conditionally expressed in airway epithelial cells during gestation and although HIF3α transgenic mice were born alive and appeared normal, their lungs showed clear abnormalities, including a post-pseudoglandular branching defect and a decreased number of alveoli. The HIF3α expressing lungs displayed reduced numbers of Clara cells, alveolar epithelial type I and type II cells. As a result of HIF3α expression, the level of Hif2α was reduced, but that of Hif1α was not affected. Two regulatory genes, Rarβ, involved in alveologenesis, and Foxp2, a transcriptional repressor of the Clara cell specific Ccsp gene, were significantly upregulated in the HIF3α expressing lungs. In addition, aberrant basal cells were observed distally as determined by the expression of Sox2 and p63. We show that Hif3α binds a conserved HRE site in the Sox2 promoter and weakly transactivated a reporter construct containing the Sox2 promoter region. Moreover, Hif3α affected the expression of genes not typically involved in the hypoxia response, providing evidence for a novel function of Hif3α beyond the hypoxia response.
Highlights
The lung originates from the primitive foregut early in the development of land dwelling organisms, and through a complex interplay of signaling molecules the future airway epithelium and surrounding mesenchyme develop into the highly structured arbor-like bronchial-vascular tree
Cellular responses to different levels of oxygen are important for development and homeostasis [6], and the most important oxygen-sensing mechanism to protect cells from oxygen toxicity is the transcriptional response mediated by Hypoxia Inducible Factors (HIF), which are expressed in the lungs [7]
It was shown that homozygous NEPAS/Hif3a knockout mice were viable, but displayed an enlarged right ventricle and impaired lung remodelling, suggesting that Hif3a plays an important role during pulmonary development
Summary
The lung originates from the primitive foregut early in the development of land dwelling organisms, and through a complex interplay of signaling molecules the future airway epithelium and surrounding mesenchyme develop into the highly structured arbor-like bronchial-vascular tree (reviewed in [1,2,3]). The PHD proteins are inactive, so the HIFa proteins are not hydroxylated and stable They will translocate to the nucleus and dimerize with HIF1b, leading to the transcription of target genes, such as EPO and VEGF, through the binding to specific DNA seqences (Hypoxia Responsive Elements, HRE) [8,35,36]. The oxygen-dependent asparaginyl hydroxylase Factor Inhibiting HIF (FIH), a member of the Fe(II) and 2-oxoglutarate-dependent dioxygenase, hydroxylates a conserved asparaginyl residue in the CTAD, preventing the association of HIFa with the p300 coactivator [37,38,39] In addition to these hydroxylation dependent regulation of HIFa isoforms, several other posttranslational modifications have been identified (for review, see [8,40,41])
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