Grant: Discovery Grants Program - Individual

A fundamental aim of my laboratory is to understand the underlying mechanisms of cellular polarity and in particular neuronal polarity. Work using polarized epithelial cells has established that three conserved core protein-protein complexes exist and are important for establishing cellular polarity in part by regulating the activity of the Hippo signaling pathway. Despite an emerging literature revealing that Hippo signaling controls cell growth and modulates cellular mechanotrasduction in non-neuronal cells, little is known about the role for Hippo signaling components in post mitotic neurons. Our NSERC funded program has focused on identifying novel polarity complexes in CNS tissues and how these function to control neuronal polarity. Our recent work has revealed a novel function for the Hippo kinase, large tumour suppressor kinase 1 (LATS1) in the stabilization of developing synapses. In non-neuronal cells, LATS1 and a related protein LATS2 function similarly in driving Hippo signaling. However, significant differences in these two proteins suggest they likely contribute to different intracellular signaling pathways. Our preliminary data reveals that in the developing nervous system, LATS1 and LATS2 have opposite expression profiles implicating LATS2 in the mature CNS. Our preliminary data also reveals that LATS2 is enriched in dendritic spines and affects both actin turnover and synapse morphology. Building on these intriguing findings, we aim to identify mechanisms by which the conserved Hippo kinase LATS2 contributes to the regulation of synaptic structural plasticity to affect neuronal function. In particular, we will: 1) Define a role for LATS2 in neuronal polarity and synaptic morphology. We will characterize how LATS2 is recruited to excitatory synapses and determine if the effects on spine morphology are kinase dependant. We will also assess the importance of LATS2 for normal cognition. 2) Characterize how LATS2 kinase activity regulates actin dynamics to regulate dendritic spine morphology. We will determine whether LATS2 directly affects actin dynamics or does so by regulating the activity of the small actin regulatory RhoGTPases, Rac, Rho or Cdc42. 3) Identify molecular pathways that function upstream of LATS2 to regulate synaptic morphology. We will test whether other known LATS2 associating proteins, KIBRA and Merlin, affect activity dependent regulation of LATS2 contributing to synapse stability.  Together this work is novel, as there have been no descriptions for the contributions of the conserved LATS kinases in post mitotic neurons. Further this work will provide mechanistic insight into the role Hippo signaling components play in regulating neuronal polarity including how these signaling components contribute to the regulation of synaptic morphology and function.