Zheng Zhou, Ph.D.
Assistant Professor, Biochemistry & Molecular Biology
Education
- Ph.D., Baylor College of Medicine
- Postdoctoral training: Massachusetts Institute of Technology
- Postdoctoral fellowships awarded by: Cancer Research Fund of the Damon Runyon-Walter Winchill Foundation, The Medical Foundation Merck/MIT Collaboration Program
Molecular Genetic Studies of Clearance of Apoptotic Cells in C. elegans
During an animal's development and adulthood many unwanted cells are eliminated by a process called "programmed cell death" or "apoptosis". Such cells undergo specific changes in appearance, die, and are quickly engulfed and digested by other cells. The engulfment step is important because dead cells can contain material that, if released, could harm neighboring cells. Both inefficient engulfment of apoptotic cells and incorrect engulfment of cells that should normally live could result in human diseases. The engulfment process utilizes mechanisms that remain largely unknown to regulate cell-cell signaling, cell-cell interaction, and cytoskeletal reorganization. These mechanisms are likely to be utilized by many other biological processes such as cell migration. Therefore, understanding the mechanisms that control engulfment has important meanings to biological and medical researches.
My laboratory is investigating how apoptotic cells are engulfed. We are working to answer the following questions: 1) How do engulfing cells recognize the apoptotic cells? What is the molecular nature of the "eat me" signal(s) presented by the apoptotic cells? 2) What are the signaling pathways that trigger and regulate the polarized extension of engulfing cell surfaces that embrace the apoptotic cells? How are the plasma membrane and the actin cytoskeleton underneath it rearranged during cell-surface extension? 3) How is an apoptotic cell efficiently degraded inside the engulfing cell? We are studying these questions using a small round worm the nematode Caenorhabditis elegans, a simple organism in which apoptotic cells are easily recognizable and genetic manipulations are well-established. Because many genes that have been identified in C. elegans resemble genes that perform analogous functions in humans, it is likely that what is learned from studying this worm will enhance the understanding of how human genes work. In C. elegans, apoptotic cells are rapidly engulfed and digested by their neighboring, living cells.
Previous genetic analyses have identified six genes that control engulfment by acting in two partially redundant pathways, ced-1, -6, -7 in one, and ced-2, -5, and -10 in the other (ced: cell death abnormal) (Figure 1).
Mutations in these genes result in defects in the engulfment of apoptotic cells and persistent "cell corpses" remain in the body (Figure 2).
Research Summary
To identify new genes involved in engulfment, I performed a large scale genetic screen for mutants containing persistent cell corpses and isolated 68 mutants. These mutants fall into four phenotypic classes. The analyses of the Class 1 mutants led me to identify a new engulfment gene, ced-12, which I cloned and found to encode a PH domain-containing protein that associates with membranes. Classes 2, 3 and 4 are new phenotypic classes and are likely to define new genes. I characterized two engulfment genes, ced-1 and ced-12, molecularly. CED-1, the protein product of ced-1, is similar to mammalian scavenger receptors and acts as an engulfing cell-specific transmembrane receptor that recognizes cell corpses.
CED-1 clusters around cell corpses (Figure 3), presumably acting to recruit downstream effectors and induce local reorganization of the actin cytoskeleton. CED-1, CED-6 and CED-7 form a signaling pathway. CED-12, the protein product of ced-12, together with CED-2 and CED-5, form a protein complex that activates CED-10, a C. elegans homolog of the mammalian Rac GTPases known to regulate cytoskeletal reorganization in many biological processes. We propose that when neighboring cell corpses are present, CED-12 acts to recruit this protein complex to the plasma membrane of the engulfing cells, and there, this complex induces local cytoskeletal reorganization via the activation of CED-10. In collaboration with Alan Hall's laboratory at University College London, we found that CED-12 and its Drosophila and mammalian counterparts could reorganize the actin cytoskeleton using a conserved mechanism.
Future Work
A major part of the immediate future work of my lab will be to continue the genetic and molecular characterizations of ced-1 and other candidate genes identified from the current screen, aiming at delineating the ced-1 pathway and other, perhaps parallel pathways. We will characterize the Class 2, 3 and 4 engulfment genes identified from the genetic screen, identify the "eat me" signals presented by cell corpses, and identify downstream targets of CED-1. We will continue to investigate the action of CED-12 and the CED-2/CED-5/CED-12 protein complex. Ultimately, we want to understand how the two signaling pathways, one involves CED-1, CED-6, and CED-7 and the other involves CED-2, CED-5, CED-10, and CED-12 converge to regulate the complex process of engulfment. In addition, we are developing a new method to visualize cell-corpse engulfment in living animals using advanced microscopic techniques. We will apply the knowledge learned from C. elegans to study the engulfment of apoptotic cells in mammals.