title: Tissue-dependent consequences of Apc inactivation on proliferation and differentiation of ciliated cell progenitors via Wnt and notch signaling.
abstract: The molecular signals that control decisions regarding progenitor/stem cell proliferation versus differentiation are not fully understood. Differentiation of motile cilia from progenitor/stem cells may offer a simple tractable model to investigate this process. Wnt and Notch represent two key signaling pathways in progenitor/stem cell behavior in a number of tissues. Adenomatous Polyposis Coli, Apc is a negative regulator of the Wnt pathway and a well known multifunctional protein. Using the cre-LoxP system we inactivated the Apc locus via Foxj1-cre, which is expressed in cells committed to ciliated cell lineage. We then characterized the consequent phenotype in two select tissues that bear motile cilia, the lung and the testis. In the lung, Apc deletion induced β-catenin accumulation and Jag1 expression in ciliated cells and by lateral induction, triggered Notch signaling in adjacent Clara cells. In the bronchiolar epithelium, absence of Apc blocked the differentiation of a subpopulation of cells committed to the ciliogenesis program. In the human pulmonary adenocarcinoma cells, Apc over-expression inhibited Jag1 expression and promoted motile ciliogenic gene expression program including Foxj1, revealing the potential mechanism. In the testis, Apc inactivation induced β-catenin accumulation in the spermatogonia, but silenced Notch signaling and depleted spermatogonial stem cells, associated with reduced proliferation, resulting in male infertility. In sum, the present comparative analysis reveals the tissue-dependent consequences of Apc inactivation on proliferation and differentiation of ciliated cell progenitors by coordinating Wnt and Notch signaling.
authors: Division of Newborn Medicine, Department of Pediatrics, Los Angeles County+University of Southern California Medical Center, Keck School of Medicine of USC, Los Angeles, California, United States of America.
authors: Aimin
authors: A
authors: Li
authors: Belinda
authors: B
authors: Chan
authors: Juan C
authors: JC
authors: Felix
authors: Yiming
authors: Y
authors: Xing
authors: Min
authors: M
authors: Li
authors: Steven L
authors: SL
authors: Brody
authors: Zea
authors: Z
authors: Borok
authors: Changgong
authors: C
authors: Li
authors: Parviz
authors: P
authors: Minoo
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D002923:Cilia; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D017353:Gene Deletion; D020868:Gene Silencing; D005854:Germ Cells / Q000378:metabolism; D059765:Homologous Recombination; D006801:Humans; D019426:Integrases / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D051880:Receptors, Notch / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D013091:Spermatogenesis / Q000235:genetics; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D013737:Testis / Q000166:cytology / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495267:CTNNB1 protein, mouse; D002135:Calcium-Binding Proteins; C481963:FOXJ1 protein, mouse; D051858:Forkhead Transcription Factors; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C045073:Cre recombinase; D019426:Integrases
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