Ligand-independent activation of the Hedgehog pathway displays non-cell autonomous proliferation during eye development in Drosophila.
Deregulation of the Hedgehog (Hh) signaling pathway is associated with the development of human cancer including medullobastoma and basal cell carcinoma. Loss of Patched or activation of Smoothened in mouse models increases the occurrence of tumors. Likewise, in a Drosophila eye model, deregulated Hedgehog signaling causes overgrowth of eye and head tissues. Surprisingly, we show that cells with deregulated Hh signaling do not or only little contribute to the tissue overgrowth. Instead, they become more sensitive to apoptosis and may eventually be eliminated. Nevertheless, these mutant cells increase proliferation in the adjacent wild-type tissue, i.e., in a non-cell autonomous manner. This non-cell autonomous effect is position-dependent and restricted to mutant cells in the anterior portion of the eye. We also observe precocious non-cell autonomous differentiation in genetic mosaics with deregulated Hh signaling. Together, these non-cell autonomous growth and differentiation phenotypes in the Drosophila eye model reveal another strategy by which oncogenes may generate a supportive micro-environment for tumor growth.
Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Audrey E
AE
Christiansen
Tian
T
Ding
Andreas
A
Bergmann
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism*; D005123:Eye / Q000166:cytology* / Q000254:growth & development* / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D016547:Kinesins / Q000235:genetics; D008024:Ligands; D051379:Mice; D009030:Mosaicism; D009154:Mutation / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction
D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D008024:Ligands; D011956:Receptors, Cell Surface; C107452:cos protein, Drosophila; C070844:ptc protein, Drosophila; D016547:Kinesins