Abrogation of Eya1/Six1 disrupts the saccular phase of lung morphogenesis and causes remodeling

Abstract

The Eya1 gene encodes a transcriptional co-activator that acts with Six1 to control the development of different organs. However, Six1-Eya1 interactions and functional roles in mesenchymal cell proliferation and differentiation as well as alveolarization during the saccular stage of lung development are still unknown. Herein, we provide the first evidence that Six1 and Eya1 act together to regulate mesenchymal development as well as alveolarization during the saccular phase of lung morphogenesis. Deletion of either or both Six1 and Eya1 genes results in a severe saccular phenotype, including defects of mesenchymal cell development and remodeling of the distal lung septae and arteries. Mutant lung histology at the saccular phase shows mesenchymal and saccular wall thickening, and abnormal proliferation of α-smooth muscle actin-positive cells, as well as increased mesenchymal/fibroblast cell differentiation, which become more sever when deleting both genes. Our study indicates that SHH but not TGF-β signaling pathway is a central mediator for the histologic alterations described in the saccular phenotype of Eya1(-/-) or Six1(-/-) lungs. Indeed, genetic reduction of SHH activity in vivo or inhibition of its activity in vitro substantially rescues lung mesenchymal and alveolar phenotype of mutant mice at the saccular phase. These findings uncover novel functions for Six1-Eya1-SHH pathway during the saccular phase of lung morphogenesis, providing a conceptual framework for future mechanistic and translational studies in this area.

EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells

“…The Hh signalling pathway is a prominent regulator of embryonic development, where Hh ligands function as morphogens to control numerous developmental processes12. Interestingly, in Drosophila eye development, hh is a direct target of sine oculis (the homologue of Six1)13 and Six1 regulates Hh/GLI signalling during lung development and in fibroblasts1415. In addition, Twist1 and Hh/GLI signalling are intimately linked during development16, and recently Twist1 and Snail1 were associated with the Hh pathway in tumour-initiating cells1718.…”

Sonic Hedgehog Signaling in the Lung. From Development to Disease

“…Eyes absent1 (EYA1) and sine oculis1 (SIX1), two homeobox transcriptions factors involved in eye development and expressed in lung epithelium and mesenchyme, were also found to affect lung development (116)(117)(118). Both Six1 -/-and Eya1 -/-lungs show a hypoplastic phenotype with branching defects, which is exaggerated in Six1 -/-;Eya1 -/-mutants.…”

The expression profile and clinic significance of the SIX family in non-small cell lung cancer

“…Specifically, decreased EYA1 and SIX1 expression during the late pseudoglandular stage involving epithelial branching and distal airway maturation led to the pulmonary hypoplasia (PH) [5]. Transgenic mouse model demonstrated that deletion of either Six1 or Eya1 genes leads to a defect of mesenchymal cell development and remodeling of the distal lung septae and arteries [6]. It has been proved that EYA1 and SIX1 played pivotal roles during lung morphogenesis [7].…”