Christian Eckmann

Controls of cell fate decisions through post-transcriptional RNA regulation

Previous and current research

Cell fate decisions are generally thought to be controlled at the transcriptional level. Recent work has illuminated principles of cell fate decisions relying on post-transcriptional gene expression especially in germline cell fate decisions, early embryogenesis and neuronal plasticity. These post-transcriptional control mechanisms share conserved regulatory trans-acting factors (RNA-binding or modifying proteins). The molecular players and nature of these control mechanisms are poorly understood and the central focus of our lab.

We have chosen the execution of germ cell fate decisions in C. elegans as our primary model system. In the developing germ line three major germ cell fate decisions (survival/death, mitosis/ meiosis, and sperm/oocyte) are executed and temporally correlated with the larval stages of the organism. Developmental stages of the germ line can be observed in living worms and are organized in a linear fashion within the gonadal tube (see cartoon). Interestingly germ cells share a common core cytoplasm (syncytium), raising a challenging cell biological question: How is information restricted to the individual cells that are pursuing different cell fate programs without being completely separated from each other? In addition to this question we are trying to understand the relationship among identified RNA regulators, often found in larger macromolecular protein complexes. How these complexes are themselves controlled and integrated into cell cycle regulation and cell differentiation remains mysterious and an area of our research.

A unique property of germ cells is the presence of non-membrane bound cytoplasmic structures, found in almost all sexual reproducing organisms, termed nuage or germplasm granules (P granules in C. elegans). Germplasm granules are ribonucleoprotein particles implicated in translational control. In the developing germ line P granules are associated with nuclear membrane and detach from it in the maturing oocyte. In the early embryo P granules co-segregate into the germline progenitor cells. We are interested in the molecular composition of germplasm granules, their role in germline development and their peculiar localization behaviors within different germ cells. In addition to classical P granules we identified non-P granular cytoplasmic particles present in the syncytium and the embryonic germplasm. We found these structures to contain a novel cytoplasmic poly-A polymerase (cPAP) and suggest that they might represent hubs of translational control. We are using the RNA-binding subunit, GLD-3, of this novel cPAP as a gateway to investigate the composition and function of these structures.

 Cell fates in the C. elegans hermaphroditic germline are established in a distal (DTC) to proximal manner. DTC, Distal tip cell (somatic); 
 TZ, transition zone (early meiosis)

 Early embrogenesis. Germplasm granules (green, and arrow), non-P granular structures positive for GLD-3 in (red, arrowhead)

Future prospects and goals

Several RNA-binding proteins have been identified but for most of them RNA targets are not known. The lab is generating tools to identify RNA targets and understand their regulation at the molecular level as well as their function in germline development. In particular we are interested in determining where in the cytoplasm post-transcriptional control is occurring. This question overlaps with another main project in the lab: to delineate the composition and nature of germplasm granules. Furthermore, we would like to understand how the life cycle of the animal influences and synchronizes germ cell fate decisions. We are pursuing possible connections to conserved signaling pathways.

Goals
To understand post-transcriptional (especially translational) control mechanisms governing cell fate decisions. We will use genetic and proteomic approaches to identify and characterize general principles and factors of control mechanisms at the molecular and cell biological level. In addition, we seek to understand the biological role of germplasm granules and their importance for the determination of the germ line, the ultimate stem cells of every sexually reproducing organism.

About

1998: PhD at the University of Vienna 1998-2003: Postdoctoral work at University of Wisconsin-Madison, USA since 2004: Group Leader at the Max Planck Institute of Molecular Cell Biology and Genetics

Selected publications

C.R. Eckmann, S. Crittenden and J. Kimble (2004): The GLD genes and NOS-3 in controlling the mitosis/meiosis decision in the C. elegans germline. Genetics. 168, 147-60.

Crittenden, S., Eckmann, Ch. R., Wang, L., Wickens, M. and Kimble, J. (2003): Balancing proliferation and differentiation in the C. elegans germ line: The roles of Notch signaling and RNA regulation. Philos Trans R Soc Lond B Biol Sci., 358, 1359-1362

Eckmann, Ch. R., Kraemer, B., Wickens, M. and Kimble, J. (2002): GLD-3, a Bicaudal-C homolog that negatively regulates FBF to control germline sex determination in C. elegans. Developmental Cell, 3, 697-710

Wang, L., Eckmann, Ch. R., Kadyk, L. C., Wickens, M. and Kimble, J. (2002): A regulatory cytoplasmic poly(A) polymerase in Caenorhabditis elegans. Nature, 419, 312-316

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