Tissue-dependent consequences of Apc inactivation on proliferation and differentiation of ciliated cell progenitors via Wnt and notch signaling. PLoS One 2013;8(4):e62215
Date
05/07/2013Pubmed ID
23646120Pubmed Central ID
PMC3639955DOI
10.1371/journal.pone.0062215Scopus ID
2-s2.0-84876983124 (requires institutional sign-in at Scopus site) 17 CitationsAbstract
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.
Author List
Li A, Chan B, Felix JC, Xing Y, Li M, Brody SL, Borok Z, Li C, Minoo PAuthor
Juan Felix MD Vice Chair, Director, Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adenomatous Polyposis Coli ProteinAnimals
Calcium-Binding Proteins
Cell Differentiation
Cell Line
Cell Proliferation
Cilia
Female
Forkhead Transcription Factors
Gene Deletion
Gene Silencing
Germ Cells
Homologous Recombination
Humans
Integrases
Intercellular Signaling Peptides and Proteins
Jagged-1 Protein
Lung
Male
Membrane Proteins
Mice
Mice, Transgenic
Organ Specificity
Receptors, Notch
Respiratory Mucosa
Serrate-Jagged Proteins
Signal Transduction
Spermatogenesis
Stem Cells
Testis
Wnt Proteins
beta Catenin
