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Title: Loss of Nkx2.8 deregulates progenitor cells in the large airways and leads to dysplasia

Author
item TIAN, JIANMIN - ALBERT EINSTEIN COLLEGE
item RADMA, MAHMOOD - AECOM
item Hnasko, Robert
item LOCKER, JOSEPH - AECOM

Submitted to: Cancer Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/1/2003
Publication Date: 11/1/2006
Citation: Tian, J., Radma, M., Hnasko, R.M., Locker, J. 2006. Loss of Nkx2.8 deregulates progenitor cells in the large airways and leads to dysplasia. Cancer Research. 1:66(21):10399-407.

Interpretive Summary: The Nkx2.8 protein has been implicated in liver cancer and the developing brain. In this report we localize this protein to a distinct subpopulation of stem cells in the lung. Using recombinant DNA technology we engineer a transgenic mouse that lacks functional Nkx2.8 and substitute a cellular marker (LacZ) that allows us to identify the cells that would normally be expressing Nkx2.8. We identify developmentally distinct respiratory and pulmonary cell types that express the Nkx2.8 cellular marker. Moreover, we show that cells expressing the Nkx2.8 cellular marker are consistent with progenitor stem cells and disruption of the Nkx2.8 gene results in increased cell expansion that leads to progressive lung pathology. This transgenic mouse represents one of the first genetic models of lung cancer and represents a unique opportunity to evaluate the role stem cells play in the development of lung cancer.

Technical Abstract: Nkx2.8, a homeodomain transcription factor, has been characterized in liver cancer and in the developing central nervous system. We now show that this factor is also expressed in the lung, where it localizes in adults to a discrete population of tracheobronchial basal cells. To target the mouse gene, the first exon was replaced by a LacZ marker gene joined to the intact 5'-untranslated region. Marker expression was observed throughout the lower respiratory tract, beginning on E11 in a few cells of the distal lung buds. The region of expression then spread upward. By neonatal day 1, expression was greatest in the large airways and the Nkx2.8-/- mice exhibited generalized tracheobronchial hyperplasia. Bromodeoxyuridine (BrdUrd) labeling studies showed that a higher rate of bronchial cell proliferation persisted at 6 to 8 months. In adults, Nkx2.8 marker expression decreased with progressive differentiation into ciliated and secretory cells. The cell localizations and patterns of coexpression with BrdUrd and differentiation markers suggest a progenitor relationship: the cells that most strongly express Nkx2.8 seem to function as tracheobronchial stem cells. Moreover, Nkx2.8 acts to limit the number of these progenitor cells because the marker-expressing population was greatly expanded in Nkx2.8-/- mice. Increased proliferation and an altered progenitor relationship caused progressive bronchial pathology, which manifested as widespread dysplasia in the large airways of 1-year-old Nkx2.8-/- mice.