Project number 20

Compartmentalized use of "growth-control-regulators" in axonal growth, branching, and synaptogenesis: Non-canonical roles of the Hippo pathway

In a series of genetic studies in Drosophila, we identified novel signaling components that are essential for spatially specific CNS synapse formation and axonal branching. Surprisingly these factors include multiple components and regulators of the Hippo pathway. Importantly, this function of the Hippo pathway does not involve any regulation of cell proliferation or cell soma growth, the classic functions of Hippo signaling. Thus, while the Hippo pathway has immensely important and well known functions in organ growth control, regeneration, and cancer, a role in neuronal wiring and synaptogenesis has not been described. The joint project of the Schmucker and Halder labs aims at testing the hypothesis that local and compartmentalized regulation of an unconventional Hippo signaling cascade in distal axon segments plays an important role in determining the correct pattern and amount of neuronal wiring and synaptogenesis. The goals of this new project are to dissect the molecular mechanisms of how this seemingly universal growth control pathway is integrated into processes of exquisite specificity, i.e. specification of spatially restricted synapse formation, requirements in axons but not in dendrites or the neuronal soma. Also, what triggers activation of Hippo signaling in axons and at synaptic sites, and does this function involve transcriptional regulation or local effects at the sites of synaptogenesis for example through regulation of local translation? Moreover, does the Hippo pathway control axon regeneration, and is experimental activation of the Hippo pathway sufficient to induce axon regeneration, similar to its effect on organ growth? These projects will involve genetic experiments in Drosophila and mouse and the student will be using high powered modern microscopy techniques such as super resolution and Correlative Light and Electron Microscopy (CLEM) as well as state of the art genome engineering and biochemistry methods.

Reagents and expertise on Hippo pathway analysis (genetics; cell culture; whole genome pathway analysis) will be provided by the Halder lab
Expertise and expertise on neuronal wiring analysis in vivo (genetics, imaging including CLEM, single neuron analysis) will be provided by the Schmucker lab.
Neuronal wiring analysis will be mostly done using fly models of the Schmucker lab, fly genetics is supervised by both, translation to vertebrate models is supervised by Halder.

hippo pathway, growth control, axon branching, synaptogenesis, neuronal regeneration

Georg Halder, VIB Center for the Biology of Disease, KU Leuven, Leuven
Dietmar Schmucker, Neuronal Wiring and Synaptic Connectivity Lab, KU Leuven, Leuven