Regulation der Zahl und des Proliferationsverhaltens von neuronalen Stammzellen während der Entwicklung des zentralen Nervensystems von Drosophila melanogaster
Final Report Abstract
Neuroblasts, the neural progenitor cells of the Drosophila central nervous system have emerged as key model system for many aspects of stem cell biology such as specification of distinct progenitor subtypes, their lineage analysis and the identfication of extrinsic and instrinsic factors which control proliferation and cell division. During development, distinct neuroblasts not only show an intricate balance between quiescence and proliferation phases but they also differ in their rate and duration of proliferation. Neuroblast proliferation is coordinated with developmental timing by systemic factors and local signals. Yet, also cell intrinsic mechanisms must exist, which allow for proper neuroblast growth as a prerequisite for continous proliferation. Recently, we have characterized two mutations, mushroom bodies tiny (mbt) and mushroom body miniature (mbm), which do not affect the overall brain anatomy but instead affect brain size, most prominently the mushroom bodies, a paired neuropil structure involved in learning and meory processes. Phenotypic analysis of mbm and mbt neuroblasts revelaed a significant decrease in cell size. Taking advantage of the complete description of the lineages of the four mushroom body neuroblasts, we could show that in mbt, neuroblasts become correctly specified during embryogenesis and divide in a normal asymmetric manner but they proliferate at reduced rates during development and finally die prematurely by apoptosis. Although Mbt function is required in neuroblasts at the cell cortex, the integration of this protein kinase into signaling processes controlling cell growth remains elusive so far. In the case of Mbm we could show that it is a novel component of the nucleolus, which is required for biogenesis of the small ribosomal subunit providing a good explanation for the impaired cell growth. Expression of mbm is dependent on the transcriptional factor Myc. Mbm becomes phosphorylated by protein kinase CK2, which obviously controls localization and/or stability of the protein. Despite these findings, the molecular function of Mbm is not known. In summary, we have characterized two proteins, which are required in neuroblasts for proper cell growth. In both cases, the major challenges will be to uncover the molecular functions in neuroblasts, their regulation during development and during the cell cycle and a differential analysis of different neuroblast lineages.
Publications
- (2004). Identification of Mushroom body miniature, a zinc finger protein implicated in brain development of Drosophila. Proc. Natl. Acad. Sci. USA 101, 14276-14281
Raabe, T., Clemens-Richter, S., Twardzik, T., Ebert, A., Gramlich, G, Heisenberg, M.
- (2006). Drosophila Pins-binding protein Mud regulates spindle-polarity coupling and centrosome organization. Nature Cell Biol. 8, 586-593
Izumi, Y., Ohta, N., Hisata, K., Raabe, T., Matsuzaki, F.
- (2009). Structural brain mutants: Mushroom body defect (Mud): A case study. J. Neurogenetics 23, 42-47
Hovhanyan, A., Raabe, T.
- The p21-activated kinase Mbt is a component of the apical protein complex in central brain neuroblasts and controls cell proliferation. Development
Melzer, J. Kraft, K.F., Urbach, R., Raabe, T.
(See online at https://doi.org/10.1242/dev.088435)
