Nuclear Dynamics in Cell and Developmental Biology
Dr Peter Askjaer
Development of an organism requires precise orchestrating of numerous biological processes. In particular, control of gene expression and accurate cell division are of paramount importance to all forms of life and involve extensive interactions between proteins and chromatin. In eukaryotic cells, access to the genome is controlled by the nuclear envelope (NE), which serves as a selective permeability barrier and chromatin organizer.
The NE consists of three major components: the nuclear membranes, the nuclear pore complexes (NPCs), and the nuclear lamina. NPCs are composed of multiple copies of approximately 30 different nucleoporins and regulate transport between the cytoplasm and the nucleus. Through a systematic depletion we have identified several nucleoporins that are essential for correct segregation of chromosomes and for reforming the NE after mitosis. For instance, we have recently discovered an interaction between the nucleoporin NUP107/NPP-5 and the Spindle Assembly Checkpoint protein MAD1. In our analysis of nucleoporins and other NE proteins we combine advanced light microscopy, genome-wide RNAi and biochemical approaches.
Interactions between the NE and chromatin can be studied in vivo using the DamID technique. Taking advantage of the genetic amenability of the nematode Caenorhabditis elegans we are probing the dynamics of these interactions during development and across genetic backgrounds that mimic human pathogenic situations. We focus our attention on genes related to NE-associated diseases, collectively known as laminopathies.
Finally, we also aim to unravel the biological function of the conserved protein kinase VRK-1. Through phosphorylation, protein kinases act as regulators of up to ~30% of the human proteome. VRK-1 substrates include chromatin proteins (e.g. BAF, histones) and transcription factors (e.g. TP53, JUN). Loss of VRK-1 activity in mammals is associated with sterility and neurological phenotypes, but the disease mechanisms are unclear. We have described specific subcellular and organogenesis defects in C. elegans mutant for vrk-1 and we aim to link these to human physiology.