The Luders group investigates the mechanisms by which cells organize their microtubule cytoskeleton and how defects in this organization are linked to disease. In recent years the group as focused on the roles of the microtubule cytoskeleton during brain development and how mutations in genes encoding components of the microtubule cytoskeleton lead to brain developmental disorders such as microcephaly. Our approach is centered on microtubule nucleation, the process by which cells generate new microtubules. Controlling the nucleation of microtubules in space and time is key to assembling ordered microtubule arrays and to their remodeling during the cell cycle and during differentiation. Currently we address the following research questions:
How are microtubules nucleated?
The main microtubule nucleator is the multi-subunit gamma-tubulin ring complex (gammaTuRC). Mutations in gammaTuRC subunits cause brain developmental defects including microcephaly, but the underlying mechanisms are poorly understood. The current ‘template’ nucleation model suggests that gammaTuRC provides a template for microtubule assembly by mimicking the end of a growing microtubule. However, recent Cryo-EM structures have revealed that gammaTuRC is not a good template and likely requires activation to become a nucleator. How this is achieved, however, is unclear. We use cell-based and biochemical approaches to study how different subunits contribute to assembly and function of gammaTuRC, with the ultimate goal to decipher the nucleation mechanism and its regulation. This will also help us understand the clinical phenotypes caused by mutations in gammaTuRC subunits.
How do MTOCs work?
Microtubule nucleation in cells is spatially restricted to microtubule organizing centers (MTOCs) such as the centrosome. Loss of centrosomal MTOC function in neural progenitors was shown to cause mitotic defects and lead to microcephaly. These defects have been linked to mutations in a growing list of centrosome genes. However, in many cases their molecular function and how they impact on the centrosomal MTOC is unknown. We aim to deconstruct MTOCs such as the centrosome, which is composed of hundreds of proteins, and identify the minimal set of proteins required to build an MTOC. This will allow us to define crucial components and activities for a better understanding of centrosomal and non-centrosomal MTOCs in cells.
How do cells organize microtubules?
Different cell types employ different mechanisms to organize microtubules. In some cells the microtubule network is mostly organized by the centrosome, in others by the Golgi or other types of non-centrosomal MTOCs. Apart from MTOC-based mechanisms some cells also employ augmin-mediated, branching nucleation. Using in vitro and in vivo models, we aim to identify novel cell type-specific nucleation pathways and cellular structures that function as MTOCs, and describe their contribution to overall microtubule organization.
How does a defective microtubule cytoskeleton cause disease?
While a large number of functional studies have identified factors required for microtubule organization, the majority was conducted in cancer cell lines, describing mostly effects on mitosis and proliferation. However, this scenario is not always relevant in the context of microtubule cytoskeleton-related diseases. We aim to address this by generating and studying disease-relevant models such as primary cells and organoids, and by revealing how impairment of the microtubule cytoskeleton can lead to distinct, context-dependent outcomes.