Tbx2 Controls Lung Growth by Direct Repression of the Cell Cycle Inhibitor Genes Cdkn1a and Cdkn1b

A considerable number of diseases in the mature lung can be related to the deregulation of (embryonic) programs that control the balance between proliferation and differentiation of cells.

Pediatric pulmonary hypoplasia is a common cause of neonatal death; consequently, a lot of effort has been put into understanding the network of signaling pathways that assure correct lung growth and development. However the mechanisms of cell cycle control during lung organogenesis were only insufficiently understood. Unraveling these is crucial to understand how tissue homeostasis in the lung is achieved and how deregulation of the cell cycle may contribute to pulmonary diseases.

We recently reported on the function of the T-box transcription factor gene Tbx2 in lung development. Tbx2-deficient mice exhibit markedly hypoplastic lungs in combination with reduced branching morphogenesis. Tbx2 mutant lungs feature decreased mesenchymal proliferation accompanied by excessive matrix deposition that indicates premature differentiation of fibroblasts. Downregulation of canonical Wnt-signaling and upregulation of the cell cycle inhibitors Cdkn1a (p21) and Cdkn1b (p27) precede these changes. Genetic depletion of Cdkn1a and Cdkn1b partially restored lung growth in Tbx2 mutant mice. In contrast, misexpression of Tbx2 in the lung mesenchyme of adult mice complementary resulted in hyperproliferation and a loss of Cdkn1a and Cdkn1b expression indicating a direct regulatory function of Tbx2 in control of these cell cycle regulators. We evaluated this presumption by ChIP experiments and showed binding of Tbx2 to the loci of Cdkn1a and Cdkn1b in vivo.

Conclusion:

Tbx2 regulates lung growth and mesenchymal differentiation by direct inhibition of Cdkn1a and Cdkn1b. Hence Tbx2 is a crucial mediator of cell cycle control during organ development in vivo.

References:

DOI: 10.1371/journal.pgen.1003189