Our laboratory is studying the mechanism and regulation of ribosome biogenesis in relation to nuclear dynamics and genetic disease. Ribosome biogenesis and nuclear transport of macromolecules are essential processes of all eukaryotic cells. Recently it has been demonstrated that mutations in proteins involved in these housekeeping functions can cause specific genetic diseases. We are therefore not only interested in how these processes function on a basic cell biological level but also how they lead to these inherited diseases.
In particular we are analyzing two proteins, Nopp140 and NAP57, implicated in ribosome biogenesis and nuclear transport by their localization to the nucleolus, the site of ribosome synthesis, and their ability to shuttle between the nucleus and the cytoplasm. Mutations in NAP57 lead to dyskeratosis congenita, an X-linked recessive bone marrow failure syndrome that causes early mortality. Mutations in TCOF1, which shares significant homology with Nopp140, cause Treacher Collins syndrome, a dominant autosomal disorder of craniofacial development. In order to understand the mechanism of these genetic diseases we are dissecting the function of Nopp140/TCOF1 and NAP57.
Nopp140 is a nuclear localization signal binding protein that shuttles between the nucleolus and the cytoplasm on highly localized tracks revealed by immunoelectron microscopy. The visualization of these tracks was particularly exciting because they may represent novel intranuclear pathways along which Nopp140 shuttles carrying nucleolar constituents. Interestingly, Nopp140-like intranuclear tracks have also been reported for the human AIDS virus protein Nef. Nopp140 is one of the most highly phosphorylated proteins in the cell and appears to use its unusual high charge density to interact with other proteins, in particular, with small nucleolar ribonucleoprotein particles (snoRNPs) involved in the modification of ribosomal RNA. Thus, Nopp140 may function in the transport through the nucleoplasm and docking of these snoRNPs onto ribosomal RNA. It is the highly phosphorylated repeat domain of Nopp140, which is shared by TCOF1.
NAP57 is a Nopp140 associated protein that is highly conserved with homologs in the genomes of all organisms sequenced to date, including bacteria. NAP57 is an integral part of a specific class of snoRNPs that is required for the pseudouridylation of ribosomal RNA. Ribosomal RNA is heavily modified, mostly by base methylation and isomerization of uridine residues to pseudouridines. All these modifications are clustered around the peptidyl transferase center of the ribosome and are thought to be important for the fine regulation of protein synthesis. While the mechanism of selection of the residues for modification has been identified, the enzymes themselves remain elusive. NAP57 is a prime candidate for the pseudouridine synthase because of its association with that specific class of snoRNPs and its homology to that bacterial enzyme.
Using these two proteins as handles, we are dissecting the molecular and cell biological aspects of ribosome biogenesis in a multitude of approaches. In particular, we study protein-protein or protein-RNA interactions using biochemical, immunological, and the yeast two/three-hybrid methods. We analyze the effects of exogenous expression of the two proteins on the host cell nuclear dynamics employing immuno-light and -electron microscopy. We exploit our identification of the yeast homologs of Nopp140 and NAP57 in genetic screens to identify additional factors involved in this conserved process.
Ultimately, these studies are not only aimed at the elucidation of ribosome biogenesis and of the two inherited diseases mentioned above, but also at the understanding of the upregulation of ribosome synthesis and the resulting nucleolar hyperactivity, which are major characteristics of every cancer cell.
References 
NCBI
PubMed search of "U.T. Meier"
Isaac, C., Yang, Y., and Meier, U.T. (1998). Nopp functions as a molecular link between the nucleolus and the coiled bodies. J. Cell Biol., (in press).
Dundr, M., Meier, U.T., Lewis, N., Rekosh, D., Hammarskjöld, M.-L., and Olson, M.O.J. (1997). A class of nonribosomal nucleolar components is located in chromosome periphery and in nucleolus-derived foci during anaphase and telophase. Chromosoma 105, 407-417.
Li, D., Meier, U.T., Dobrowolska, G., and Krebs, E.G. (1997). Specific interaction between casein kinase 2 and the nucleolar protein Nopp140. J. Biol. Chem. 272, 3773-3779.
Meier, U.T. (1996). Comparison of the rat nucleolar protein Nopp140 to its yeast homolog SRP40: Differential phosphorylation in vertebrates and yeast. J. Biol. Chem. 271, 19376-19384.
Meier, U.T., and Blobel, G. (1994) NAP57, a mammalian nucleolar protein with a putative homolog in yeast and bacteria. J. Cell Biol. 127, 1505 - 1514.
Meier, U.T., and Blobel, G. (1992) Nopp140 shuttles on tracks between nucleolus and cytoplasm. Cell 70, 127 - 138.