Non-autonomous crosstalk between the Jak/Stat and EGFR pathways mediates Apc1-driven intestinal stem cell hyperplasia in the Drosophila adult midgut

Cordero, J. B., Stefanatos, R. K., Myant, K., Vidal, M. and Sansom, O. J. (2012) Non-autonomous crosstalk between the Jak/Stat and EGFR pathways mediates Apc1-driven intestinal stem cell hyperplasia in the Drosophila adult midgut. Development, 139(24), pp. 4524-4535. (doi:10.1242/dev.078261)

Cordero, J. B., Stefanatos, R. K., Myant, K., Vidal, M. and Sansom, O. J. (2012) Non-autonomous crosstalk between the Jak/Stat and EGFR pathways mediates Apc1-driven intestinal stem cell hyperplasia in the Drosophila adult midgut. Development, 139(24), pp. 4524-4535. (doi:10.1242/dev.078261)

Full text not currently available from Enlighten.

Abstract

Inactivating mutations within adenomatous polyposis coli (APC), a negative regulator of Wnt signaling, are responsible for most sporadic and hereditary forms of colorectal cancer (CRC). Here, we use the adult Drosophila midgut as a model system to investigate the molecular events that mediate intestinal hyperplasia following loss of Apc in the intestine. Our results indicate that the conserved Wnt target Myc and its binding partner Max are required for the initiation and maintenance of intestinal stem cell (ISC) hyperproliferation following Apc1 loss. Importantly, we find that loss of Apc1 leads to the production of the interleukin-like ligands Upd2/3 and the EGF-like Spitz in a Myc-dependent manner. Loss of Apc1 or high Wg in ISCs results in non-cell-autonomous upregulation of upd3 in enterocytes and subsequent activation of Jak/Stat signaling in ISCs. Crucially, knocking down Jak/Stat or Spitz/EGFR signaling suppresses Apc1-dependent ISC hyperproliferation. In summary, our results uncover a novel non-cell-autonomous interplay between Wnt/Myc, EGFR and Jak/Stat signaling in the regulation of intestinal hyperproliferation. Furthermore, we present evidence suggesting potential conservation in mouse models and human CRC. Therefore, the Drosophila adult midgut proves to be a powerful genetic system to identify novel mediators of APC phenotypes in the intestine.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cordero, Dr Julia and Vidal, Dr Marcos and Myant, Dr Kevin and Stefanatos, Miss Rhoda and Sansom, Professor Owen
Authors: Cordero, J. B., Stefanatos, R. K., Myant, K., Vidal, M., and Sansom, O. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Development
Publisher:Company of Biologists
ISSN:0950-1991
ISSN (Online):1477-9129

University Staff: Request a correction | Enlighten Editors: Update this record