Myb permits multilineage airway epithelial cell differentiation.
The epithelium of the pulmonary airway is specially differentiated to provide defense against environmental insults, but also subject to dysregulated differentiation that results in lung disease. The current paradigm for airway epithelial differentiation is a one-step program whereby a p63(+) basal epithelial progenitor cell generates a ciliated or secretory cell lineage, but the cue for this transition and whether there are intermediate steps are poorly defined. Here, we identify transcription factor Myb as a key regulator that permits early multilineage differentiation of airway epithelial cells. Myb(+) cells were identified as p63(-) and therefore distinct from basal progenitor cells, but were still negative for markers of differentiation. Myb RNAi treatment of primary-culture airway epithelial cells and Myb gene deletion in mice resulted in a p63(-) population with failed maturation of Foxj1(+) ciliated cells as well as Scbg1a1(+) and Muc5ac(+) secretory cells. Consistent with these findings, analysis of whole genome expression of Myb-deficient cells identified Myb-dependent programs for ciliated and secretory cell differentiation. Myb(+) cells were rare in human airways but were increased in regions of ciliated cells and mucous cell hyperplasia in samples from subjects with chronic obstructive pulmonary disease. Together, the results show that a p63(-) Myb(+) population of airway epithelial cells represents a distinct intermediate stage of differentiation that is required under normal conditions and may be heightened in airway disease.
['Pan|Jie-Hong|JH|', 'Adair-Kirk|Tracy L|TL|', 'Patel|Anand C|AC|', 'Huang|Tao|T|', 'Yozamp|Nicholas S|NS|', 'Xu|Jian|J|', 'Reddy|E Premkumar|EP|', 'Byers|Derek E|DE|', 'Pierce|Richard A|RA|', 'Holtzman|Michael J|MJ|', 'Brody|Steven L|SL|']
D000818:Animals D002454:Cell Differentiation D019070:Cell Lineage D002478:Cells, Cultured D004847:Epithelial Cells D004848:Epithelium D006801:Humans D051379:Mice D020598:Proto-Oncogene Proteins c-myb D020545:Respiratory Mucosa D012137:Respiratory System D013234:Stem Cells
Cells Cell lineage Chronic obstructive Pulmonary disease Cilia Cultured Respiratory system Secretoglobins