Norbert Perrimon

Department of Genetics
Harvard Medical School, Howard Hughes Medical Institute

Broad Institute
New Research Building, Room 336
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: (617) 432-7672
Fax: (617) 432-7688
Email: perrimon@receptor.med.harvard.edu
Web Page: The Perrimon Lab Page

The central thesis of Developmental Biology is to understand how organisms grow and develop. In the past 30 years, studies using genetically tractable model organisms have led to a detailed understanding of the genetic mechanisms involved in the control of developmental events as illustrated by our intimate knowledge of patterning and morphogenesis. The next big questions are to understand how complex phenotypes arise in the context of the whole organism, and how the programs regulating their development and function are influenced by genetic background and environment. For example, little is understood on how the simultaneous growth and differentiation of different tissues is coordinated and on how within an organ the development of different cell types and tissues is integrated. To address some of these questions, we have initiated a number of studies on muscle growth during Drosophila larval development as this system provides unique opportunities to identify molecular mechanisms that link physiology, cell biology and cell differentiation. In addition, analysis of muscle growth and homeostasis may also shed light on the control of muscle wasting.

We are currently addressing a number of questions with regards to muscle growth and its maintenance. First, although many of the proteins that constitute the sarcomeres are known, the mechanisms that regulate their assembly at the muscle edges are not. Second, we are characterizing the extent to which muscle growth can adjust to the physiological milieu and how this homeostatic response correlates with a change in protein translation and gene expression. In particular, as microRNAs have been implicated in muscle growth we wish to understand the role of these small non-coding RNAs in protein translation. Third, to address how muscles sense fluctuations in hemolymph nutrients (amino acids, glucose,
triglycerides) that accompany changes in diet, we are focusing on the role of the Insulin pathway in the control of the assembly of sarcomeres and autophagy in muscle cells.

To address these issues, we are using a variety of state of the art technologies. In particular, to identify genes involved
in sarcomere organization and growth we are conducting RNA interference (RNAi) screens using our high-throughput genome-wide screening platform (http://flyrnai.org/) in cultured Drosophila primary muscle cells under various nutrient conditions. Cells isolated from gastrula differentiate into muscles within hours and are sensitive to RNAi such that genes that affect growth and sarcomere differentiation can be readily identified. To facilitate the analysis of the genome-wide screens, we are developing algorithms for automated image analyses that provide quantitation of cellular features describing muscle growth and shape. Further, to complement the tissue culture approach and provide validation of the genes identified in the RNAi screens, we are building a large collection of transgenic UAS-hairpin RNAi lines to knockdown gene function exclusively in larval muscles using muscle-specific Gal4 drivers. Finally, we are building a comprehensive network of the genes involved in the regulation of growth and homeostasis to provide a "system level" understanding.

References:

• Micchelli, C. and Perrimon, N. (2006) Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature. 439, 475-479.
• Gibson, M. C. Patel, A., Nagpal, R. and Perrimon, N. (2006) The emergence of geometric order in proliferating metazoan epithelia. Nature 442. 1038-1041.
• Friedman, A. and Perrimon, N. (2006) A functional RNAi screen for regulators of receptor tyrosine kinase and ERK signaling. Nature 444, 230-234.
• Bakal, C., Aach, J., Church, G. and Perrimon, N. (2007) Defining the components of local signaling networks that regulate cell morphology using quantitative morphological signatures. Science. In Press.