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Signaling via Alk5 Controls Ontogeny of Lung Clara Cells

Yiming Xing¹, Changgong Li¹, Aimin Li¹, Somyoth Sridurongrit², Caterina Tiozzo¹, Saverio Bellusci³, Zea Borok⁴, Vesa Kaartinen² & Parviz Minoo¹

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1. University of Southern California
2. University of Michigan
3. Saban Research Institute of Childrens Hospital Los Angeles
4. Will Rogers Institute of Pulmonary Research

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Document Type:

Manuscript

Date:

Received 07 April 2009 18:29 UTC; Posted 08 April 2009

Subjects:

Genetics & Genomics, Molecular Cell Biology

Tags:

• lung
• Clara cell
• Alk5

Abstract:

Clara cells, together with ciliated and pulmonary neuroendocrine cells, make up the epithelium of the bronchioles along the conducting airways. Clara cells are also known as Progenitor/Stem cells during lung regeneration after injury. The mechanisms of Clara cell differentiation are largely unknown. Transforming growth factor-beta is a multifunctional molecule with roles in normal development and disease pathogenesis. In this study, we deleted the TGF-β type I receptor, Alk5 in the embryonic lung epithelium using Gata5-Cre mice. Absence of Alk5 blocked Clara cell differentiation but had no effect on ciliated or pulmonary neuroendocrine cells. Hairy/Enhancer of Split-1, which is expressed in Clara cell putative "progenitors" was found to be a downstream target of Alk5 in vivo and in vitro. Loss of Alk5-mediated signaling also stimulated Pten gene expression and inhibited ERK phosphorylation in vivo. Using lung epithelial cells, we show that Alk5-regulated Hes1 expression is stimulated through Pten, MEK/ERK and PI3K/AKT pathways. Thus, the signaling pathway by which TGF-β/ALK5 regulates Clara cell differentiation may entail inhibition of Pten expression, which in turn activates ERK and AKT phosphorylation.

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This document is licensed to the public under the Creative Commons Attribution 3.0 License

How to cite this document:

Xing, Yiming, Li, Changgong, Li, Aimin, Sridurongrit, Somyoth, Tiozzo, Caterina, Bellusci, Saverio, Borok, Zea, Kaartinen, Vesa, and Minoo, Parviz. Signaling via Alk5 Controls Ontogeny of Lung Clara Cells. Available from Nature Precedings <http://hdl.handle.net/10101/npre.2009.3036.1> (2009)

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