In this project we investigate the role of p21 activated kinase Mbt/PAK4 in neurogenesis and neurodegeneration. In the Drosophila eye, Mbt has an essential role in morphogenetic processes during the final differentiation of photoreceptor cells especially regarding adherens junctions morphogenesis and dynamics (Menzel, et al., 2007; Schneeberger, et al., 2003). Recently we showed that formation of isolated N-Cadherin adherens junctions during eye development requires a proper balance between the promoting effects of Mbt and the inhibiting influences of non-receptor tyrosine kinases SRC. Mbt is required in photoreceptor R3/R4 for zipping the N-Cadherin adherens junctions (Pütz, 2019).
In the developing brain, Mbt function is needed for proper neuroblast proliferation. Precisely, cell size and mitotic activity are significantly reduced in mbt mutant neuroblasts (Melzer, et al., 2013). In the last decade p21 activated kinase were shown to be important for several neurodegenerative disorders, by which the project shifts to the question of whether Mbt in addition to its role during development and neurogenesis also have a neuroprotective function.
We found evidence for a causative relationship between loss of Mbt and the appearance of Parkinson´s disease like symptoms in Drosophila, including age-dependent climbing performance and sleep fragmentation.
Pütz S.M., Kram J., Rauh E., Kaiser S., Toews R., Lueningschroer-Wang Y, Rieger D., Raabe T. (2021) Loss of p21-activated kinase Mbt/PAK4 causes Parkinson-like phenotypes in Drosophila. Disease Models Mech. 14, dmm047811
Pütz, S. M. (2019). Mbt/PAK4 together with SRC modulates N-Cadherin adherens junctions in the developing Drosophila eye. Biol Open 8.
Melzer, J., Kraft, K.F., Urbach, R., and Raabe, T. (2013). The p21-activated kinase Mbt is a component of the apical protein complex in central brain neuroblasts and controls cell proliferation. Development 140, 1871-81.
Menzel, N., Schneeberger, D., and Raabe, T. (2007). The Drosophila p21 activated kinase Mbt regulates the actin cytoskeleton and adherens junctions to control photoreceptor cell morphogenesis. Mech Dev 124, 78-90.
Schneeberger, D., and Raabe, T. (2003). Mbt, a Drosophila PAK protein, combines with Cdc42 to regulate photoreceptor cell morphogenesis. Development 130, 427-37.