How do organs know when to stop growing?

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.

Recent publications

• Childress JL, Acar M, Tao C, Halder G (2006). Lethal giant discs, a novel C2 domain protein, restricts Notch activation during endocytosis. Current Biology 16:2228–33.
  
  
• 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. Proc Natl Acad Sci USA 103:17225–30.
  
  
• Willecke M, Hamaratoglu F, Kango-Singh M, Udan R, Chen CL, Tao C, Zhang X, and Halder G (2006). The Fat Cadherin acts through the Hippo tumor suppressor pathway to regulate tissue size. Current Biology 16:2090–100.
  
  
• Nolo R, Morrison C, Tao C, Zhang X, Halder G (2006). The bantam microRNA is a target of the Hippo tumor suppressor pathway. Current Biology 16:1895–904.
  
  
• 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. J Infect Dis 193(7):1014–22.
  
  
• Hamaratoglu F, Kango-Singh M, Nolo R, Hyun E, Tao C, Jafar-Nejad H, and 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.
  
  
• Eder AM, Xiaomei S, Rosen DG, Nolden L, Cheng KW, Lahad JP, Kango-Singh M, Lu KH, Warneke CL, Atkinson EN, Kuo W, Gray JW, Yin JCP, Liu J, Halder G, and Mills GB (2005). Atypical PKC iota is implicated as a novel oncogene contributing to poor prognosis through loss of apical-basal polarity and Cyclin E overexpression in ovarian and breast cancer. Proc. Natl. Acad. Sci. USA 102(35): 12519–12524.
  
  
• Lionakis MS, Lewis RE, May GS, Wiederhold NP, Albert ND, Halder G, Kontoyiannis DP (2005). Toll-deficient Drosophila flies as a fast, high-throughput model for the study of antifungal drug efficacy against invasive aspergillosis and Aspergillus virulence. J. Infectious Disease 191(7):1188–95.
  
  
• Kango-Singh, M., and G. Halder (2004). Drosophila as an emerging model to study metastasis. Genome Biology 5:216–216.3.
  
  
• Udan, R., M. Kango-Singh, R. Nolo., C. Tao, and G. Halder (2003). Hippo promotes cell proliferation arrest and apoptosis in the Salvador/Warts pathway. Nature Cell Biology 5:914–920.
  
  
• Kango-Singh, M, R. Nolo., C. Tao, P. Verstreken, P.R. Hiesinger, H.J,. Bellen and G. Halder (2002).Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila. Development 129:5719–5730.

Last updated 02/12/2007