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How do organs know when to stop growing?
(Growth control, regeneration, tumor suppressor genes, Drosophila genetics)
The regulation of organ size is fundamental to animal development, yet remarkably little is known about the
mechanisms that control organ size. How do cells know when to stop dividing after an organ has reached its proper size? How
do injured organs regenerate missing or damaged parts, and how do cells sense that part of an organ is missing? The answers
to these questions are currently unknown, but a common theme appears to be that neighboring cells signal to each other to
regulate cell proliferation. What are these signals and how do they regulate organ growth? We have chosen to use the fruit
fly Drosophila as a model system to address these questions. The combination of the powerful genetic tools available
in Drosophila and the capability of its developing tissues to regenerate make this a superb system in which to study
the regulation of organ size.
Through a genome wide genetic screen in Drosophila to identify new growth control genes, we discovered a new
signaling pathway, the Hippo pathway, which is essential for the development of properly-sized organs. Animals carrying
mutations in Hippo pathway components develop severely overgrown adult structures and have tumorous outgrowths. Mutant
tissues overgrow because hippo mutant cells continue to proliferate beyond normal organ size and because mutant cells
are resistant to the signals that would normally eliminate extra cells. Hippo signaling thus acts as a tumor suppressor
pathway in Drosophila.
Over the last few years we have identified several components of the Hippo signal transduction pathway, including
Hippo, which is a protein kinase and Merlin, the homolog of the human tumor suppressor gene Neurofibromatosis Type 2. Most
interestingly, we have recently identified a cell surface receptor that regulates the activity of the Hippo pathway: the
atypical Cadherin Fat.
We now want to find out how the activity of Fat is regulated and what ligands signal through Fat to regulate organ
growth. Also, how is the Hippo pathway involved in the regeneration of damaged tissues and how does Hippo signaling regulate
organ growth?
To investigate these issues, we have conducted genetic screens to isolate new mutants with defective organ growth. We
are currently cloning the corresponding genes and investigating whether they function in the Hippo pathway or other, novel
growth control pathways. We study the function of these genes using a variety of methods, including targeted gene expression,
conditional knock-outs, immunofluorescence and confocal microscopy.
Interestingly, all known Hippo pathway components are highly conserved in vertebrates where they also appear to act as
tumor suppressor genes. Thus, studying their functions in Drosophila will likely provide insights into the regulation
of vertebrate organ growth.
Selected Publications
Kango-Singh M, Nolo R, Tao C, Verstreken P, Hiesinger PR, Bellen HJ, Halder G (2002) Shar-pei mediates
cell proliferation arrest during imaginal disc growth in Drosophila. Development 129:5719-5730.
Udan RS, Kango-Singh M, Nolo R, Tao C, Halder G (2003) Hippo promotes proliferation arrest and apoptosis in the
Salvador/Warts pathway. Nature Cell Biology 5:914-920.
Kango-Singh M, Halder G (2004) Drosophila as an emerging model to study metastasis. Genome
Biology 5:216.
Eder AM, Sui X, Rosen DG, Nolden LK, Cheng KW, Lahad JP, Kango-Singh M, Lu KH, Warneke CL, Atkinson EN, Bedrosian I,
Keyomarsi K, Kuo WL, Gray JW, Yin JC, Liu J, Halder G, Mills GB (2005) Atypical PKCι contributes to poor prognosis
through loss of apical-basal polarity and cyclin E overexpression in ovarian cancer. Proceedings of the National Academy of
Sciences U.S.A. 102:12519-12524.
Hamaratoglu F, Willecke M, Kango-Singh M, Nolo R, Hyun E, Tao C, Jafar-Nejad H, Halder G (2006) The tumour-
suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and
apoptosis. Nature Cell Biology 8:27-36.
Chamilos G, Lionakis MS, Lewis RE, Lopez-Ribot JL, Saville SP, Albert ND, Halder G, Kontoyiannis DP (2006)
Drosophila melanogaster as a facile model for large-scale studies of virulence mechanisms and antifungal drug efficacy
in Candida species. Journal of Infectious Diseases 193:1014-1022.
Nolo R, Morrison CM, Tao C, Zhang X, Halder G (2006) The bantam microRNA is a target of the hippo
tumor-suppressor pathway. Current Biology 16:1895-1904.
Willecke M, Hamaratoglu F, Kango-Singh M, Udan R, Chen CL, Tao C, Zhang X, Halder G (2006) The fat cadherin acts
through the hippo tumor-suppressor pathway to regulate tissue size. Current Biology 16:2090-2100.
Anbanandam A, Albarado DC, Nguyen CT, Halder G, Gao X, Veeraraghavan S (2006) Insights into transcription
enhancer factor 1 (TEF-1) activity from the solution structure of the TEA domain. Proceedings of the National Academy of
Sciences U.S.A. 103:17225-17230.
Childress JL, Acar M, Tao C, Halder G (2006) Lethal giant discs, a novel C2-domain protein, restricts Notch
activation during endocytosis. Current Biology 16:2228-2233.
Contact Information
- Georg Halder, Ph.D.
- Department of Biochemistry and Molecular Biology
- The University of Texas
- M.D. Anderson Cancer Center
- 1515 Holcombe Boulevard, S11.8316A
- Houston, Texas 77030, U.S.A.
- Tel: (713) 834-6288
- Fax: (713) 834-6266
- E-mail: ghalder@mdanderson.org
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