Yale Department of Genetics, Faculty, Lynn Cooley

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Lynn Cooley

Professor of Genetics, Cell Biology and Molecular, Cellular & Developmental Biology; Director, Combined Programs in the Biological and Biomedical Sciences

* B.A. Connecticut College 1976;
* Ph.D. University of Texas at Austin 1984

Research Interests:

Molecular Genetics of Drosophila Oogenesis
Polarized Intercellular Transport of Proteins
Actin Cytoskeleton Regulation and Function

Honors:

* Pew Scholar Award

The earliest steps in embryonic development rely on maternal factors deposited into eggs during oogenesis. Our research is focused on understanding how maternal components are made and delivered to oocytes during Drosophila oogenesis. By studying mutants with incomplete oocyte growth, we have found that key steps during oogenesis rely on precise regulation of the actin cytoskeleton. For example, the junctions called ring canals that connect growing oocytes with their nurse cells are stabilized by a special population of bundled actin filaments anchored at the plasma membrane of each ring canal. Using a new protein-trapping strategy, we have found that the movement of maternal proteins through ring canals is highly regulated. We are actively characterizing the mechanism of sorting proteins between nurse cells and the oocyte.

Current projects:

Ring canals. Ring canals form between the direct descendants of germline stem cells in animals, both males and females, including humans. The function of ring canals is best understood in insects where they allow movement of cytoplasmic components between joined cells. Interestingly, ring canals are also present in somatic cells in Drosophila where their function is not known. In all cases, ring canal formation begins with an arrested mitotic cleavage furrow. We are working on several aspects of ring canal formation, cell biology and function.

Figure 1 (ring canal section). Confocal image of a single Drosophila ring canal. Filamentous actin (green) is concentrated at the ring canal, and also present at surrounding plasma membrane. The Hts ring canal protein (red) is located specifically at ring canals.

Figure 2 (protein sorting section). A. An egg chamber has 15 nurse cells and one oocyte surrounded by follicle cells. Cytoplasm moves through ring canals into the oocyte during oogenesis. B. One protein identified as a GFP fusion protein in our protein trapping screen that is specifically transported into the oocyte.

Formation. The Drosophila hts gene is required for the earliest step of ring canal formation. Mutations in hts affect both the fusome, a membranous organelle present in germline stem cells and mitotically proliferating germline cells, and ring canals. Extensive characterization of the hts gene has revealed that one of the hts mRNAs encodes a precursor protein that is cleave in half to produce a fusome protein and a ring canals protein. We are characterizing both the cleavage site and the function of the two mature cleavage products.
Cell biology. Drosophila ring canals expand during development to reach a final diameter 10,000 times greater than gap junctions. The dramatic growth of ring canals during oogenesis requires many of the same proteins that power cell motility, suggesting that the actin dynamics accompanying ring canal growth resemble the behavior of actin at the leading edge of motile cells. While new F-actin is polymerized at the outer margin of growing ring canals, old F-actin is disassembled on the lumen side of ring canals. We are studying mechanisms for both adding and subtracting actin from ring canals during development.
Somatic ring canals. The prevalence of ring canals in non-germline cells in animal tissues is unknown. In Drosophila, somatic ring canals have been found in several epithelial populations including the follicle cells of egg chambers and imaginal discs within larvae where they may coordinate cell behaviors. These somatic ring canals are much smaller than germline ring canals and contain a different spectrum of proteins. We are characterizing the components of somatic ring canals using immunofluorescence microscopy, immuno-electron microscopy. To determine the role of somatic ring canals, we are carrying out genetic analysis of ring canal components.

Protein sorting in egg chambers. Polarized cells such as epithelial and nerve cells must sort proteins to specific sub-cellular locations. The Drosophila egg chamber is a highly polarized structure with nurse cells at one end and an oocyte at the other. The nurse cells synthesize and transport huge amounts of maternal products (including organelles) into the oocyte through stable intracellular bridges called ring canals that are up to 10,000 times larger in diameter than gap junctions. Thus, the egg chamber is analogous to an enormous polarized cell. Recently, we have found compelling evidence indicating that the sorting of certain proteins in the oocyte is highly regulated. In other words, protein movement through ring canals into the oocyte is not just due to bulk flow but is also a result of a controlled selection process. By studying GFP-tagged proteins, we can see that some proteins are sequestered in the nurse cells while others move rapidly and specifically into the oocyte. We are defining the protein sequences necessary for specific transport and the transport machinery required for moving the proteins into the oocyte.

Representative Publications:

Kelso, R.J., Buszczak, M, Quinones, A.T., Castiblanco, C., Mazzalupo, S. and Cooley, L. (2004) Flytrap, a database documenting a GFP protein-trap insertion screen in Drosophila melanogaster. Nucl. Acids. Res 32: 1-3.

Mermall, V., Bonafé, N., Jones, L., Sellers, J.R., Cooley, L, and Mooseker, M.S. (2005) Drosophila Myosin V is required for larval development and spermatid individualization. Devel. Biol. 286: 238-255.

Mazzalupo, S. and Cooley, L. (2006) Illuminating the role of caspases during Drosophila oogenesis. Cell Death & Differentiation 13: 1950-1959.

Petrella, L., Smith-Leiker, T. and Cooley, L. The Ovhts polyprotein produces fusome and ring canal proteins required for Drosophila oogenesis. (2007) Development 134: 703-712.

Lee, S. and Cooley, L. (2007) jagunal is required for reorganizing the endoplasmic reticulum during Drosophila oogenesis. J. Cell Biol. 176: 941-952.

Quiñones-Coello, A.T., Petrella, L.N., Ayers, K., Melillo, A., Mazzalupo, S., Hudson, A.M., Wang, S., Castiblanco, C., Buszczak, M., Hoskins, R.A., and Cooley, L. (2007) Exploring strategies for protein trapping in Drosophila. Genetics 175: 1089-1104.

Contact Information:

email lynn.cooley@yale.edu
websites http://info.med.yale.edu/cooley/ and http://flytrap.med.yale.edu


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