Regulation of cell growth and proliferation of neural progenitor cells in the central brain of Drosophila melanogaster by protein kinase Mbt and the nucleolar protein Mbm.

神经母细胞是发育中的果蝇中枢神经系统的神经祖细胞，已成为干细胞生物学许多方面的关键模型系统，如不同祖细胞亚型的规范，它们的谱系分析以及影响神经母细胞增殖的外在和内在因素的鉴定。神经母细胞在发育过程中的增殖受到亚型特异性增殖和静止阶段以及时间模式机制的严格控制，从而依次产生正确数量的不同神经元类型。神经母细胞增殖还受到全身因素和局部信号的影响，最终保证整个机体的协调发育。然而，细胞的内在信息也必须整合，这使得正常的神经母细胞生长成为持续增殖的先决条件。最近，我们发现了两种突变体，蘑菇体微小（mbt）和蘑菇体微型（mbm），它们不影响一般的大脑组织，而是减少了整个大脑的大小，这在蘑菇体中最为明显。Mbm和mbt神经母细胞以正常的不对称方式分裂，但其增殖能力受损，这与细胞大小减小有关。在皮质定位蛋白激酶Mbt的情况下，主要目标将是识别神经母细胞中的上游调节因子和下游效应因子，主要强调RhoGTPase依赖的信号过程和整合到系统生长控制信号中。在Mbm的情况下，我们想要澄清其核仁在核糖体生物发生中的功能。Myc对mbm的转录调控和蛋白激酶CK2对mbm的磷酸化暗示mbm是系统和细胞内在生长信号的整合点，这将通过遗传和生化实验进行验证。

Neuroblasts, the neural progenitor cells of the developing 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 identification of extrinsic and intrinsic factors, which influence neuroblast proliferation. Proliferation of neuroblasts during development is strictly controlled by subtype-specific proliferation and quiescence phases and by temporal patterning mechanisms to sequentially generate the right number of different neuron types. Neuroblast proliferation is also influenced by systemic factors and local signals to finally ensure coordinated development of the whole organism. Yet, also cell intrinsic information must be integrated, which allow for proper neuroblast growth as a prerequisite for continuous proliferation. Recently, we have characterized two mutants, mushroom bodies tiny (mbt) and mushroom body miniature (mbm), which do not affect the general brain organization but instead reduce the overall brain size, which is most evident for the mushroom bodies. Mbm and mbt neuroblasts divide in a normal asymmetric manner but are impaired in their proliferative capacity, which correlates with a decrease in cell size. In the case of the cortical localized protein kinase Mbt, the major objective will be to identify upstream regulators and downstream effectors in neuroblasts with a major emphasis on RhoGTPase dependent signaling processes and integration into systemic growth control signals. In the case of Mbm, we want to clarify its nucleolar function in ribosome biogenesis. The transcriptional regulation of the mbm by Myc and the phosphorylation of Mbm by protein kinase CK2 implicate Mbm as integration point of systemic and cell intrinsic growth signals, which will be tested by genetic and biochemical experiments.