title: Primary cilia regulate Gli/Hedgehog activation in pancreas.
abstract: Previous studies have suggested that defects in pancreatic epithelium caused by activation of the Hedgehog (Hh) signaling pathway are secondary to changes in the differentiation state of the surrounding mesenchyme. However, recent results describe a role of the pathway in pancreatic epithelium, both during development and in adult tissue during neoplastic transformation. To determine the consequences of epithelial Hh activation during pancreas development, we employed a transgenic mouse model in which an activated version of GLI2, a transcriptional mediator of the pathway, is overexpressed specifically in the pancreatic epithelium. Surprisingly, efficient Hh activation was not observed in these transgenic mice, indicating the presence of physiological mechanisms within pancreas epithelium that prevent full Hh activation. Additional studies revealed that primary cilia regulate the level of Hh activation, and that ablation of these cellular organelles is sufficient to cause significant up-regulation of the Hh pathway in pancreata of mice overexpressing GLI2. As a consequence of overt Hh activation, we observe profound morphological changes in both the exocrine and endocrine pancreas. Increased Hh activity also induced the expansion of an undifferentiated cell population expressing progenitor markers. Thus, our findings suggest that Hh signaling plays a critical role in regulating pancreatic epithelial plasticity.
authors.affiliation: Diabetes Center, Department of Medicine, University of California, San Francisco, CA 94143, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Cervantes
authors.forename: Janet
authors.initials: J
authors.lastname: Lau
authors.forename: David A
authors.initials: DA
authors.lastname: Cano
authors.forename: Cecilia
authors.initials: C
authors.lastname: Borromeo-Austin
authors.forename: Matthias
authors.initials: M
authors.lastname: Hebrok
mesh_terms: D000818:Animals; D001483:Base Sequence; D002923:Cilia / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000254:growth & development / Q000378:metabolism / Q000648:ultrastructure; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D000075746:Zinc Finger Protein Gli2
chemical_list: D017931:DNA Primers; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D000075746:Zinc Finger Protein Gli2