Critical role of p63 in the development of a normal esophageal and tracheobronchial epithelium

1 Cell Biology Section, Division of Intramural Research, and 2 Laboratory of Pathology, National Institute of Environmental Health Sciences, Research Triangle Park 27709; 3 Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina, Chapel Hill, North Carolina 27599; 4 Experimental Pathology Section, Cell and Cancer Biology Branch, National Cancer Institute, Rockville, Maryland 20850; and 5 Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel 76100 Submitted 20 June 2003 ; accepted in final form 22 February 2004 The trachea and esophagus originate from the foregut endoderm during early embryonic development. Their epithelia undergo a series of changes involving the differentiation of stem cells into unique cell types and ultimately forming the mature epithelia. In this study, we monitored the expression of p63 in the esophagus and the trachea during development and examined in detail morphogenesis in p63 –/– mice. At embryonic day 15.5 (E15.5), the esophageal and tracheobronchial epithelia contain two to three layers of cells; however, only the progenitor cells express p63. These progenitor cells differentiate first into ciliated cells (p63 – / -tubulin IV + ) and after birth into mature basal cells (p63 + /K14 + /K5 + /BS-I-B4 + ). In the adult pseudostratified, columnar tracheal epithelium, K14 + /K5 + /BS-I-B4 + basal cells stain most intensely for p63, whereas ciliated and mucosecretory cells are negative. In stratified squamous esophageal epithelium and during squamous metaplasia in the trachea, cells in the basal layer stain strongest for p63, whereas p63 staining declines progressively in transient amplifying and squamous differentiated cells. Generally, p63 expression is restricted to human squamous cell carcinomas, and adenocarcinomas and Barrett's metaplasia do not stain for p63. Examination of morphogenesis in newborn p63 –/– mice showed an abnormal persistence of ciliated cells in the esophagus. Significantly, in both tissues, lack of p63 expression results in the development of a highly ordered, columnar ciliated epithelium deficient in basal cells. These observations indicate that p63 plays a critical role in the development of normal esophageal and tracheobronchial epithelia and appears to control the commitment of early stem cells into basal cell progeny and the maintenance of basal cells. retinoic acid; stem cell; carcinoma; basal cell; differentiation Address for reprint r