Precise dendrite patterning is critical for the wiring and function of the entire nervous system. Proper dendrite morphogenesis determines the properties and strength of synaptic or sensory information a neuron will receive. Furthermore, deficits in dendritic development and function are observed in many neurodevelopmental disorders. Therefore, a better understanding of how the neuron establishes its dendrite morphology during development is necessary and will also provide insights into normal developmental pathways that may be perturbed in certain disorders. Using the Drosophila dendritic arborization (da) sensory neurons, we performed a candidate-based genetic screen to identify molecules that can regulate dendritic arbor morphology. This thesis work focuses on the examination of two candidate mutations identified by genetic screens performed in the lab.
In Chapter 2 we examine the role of the semaphorin signaling in regulating dendrite arbor patterning by restricting dendrites in a 2D space. Loss of semaphorin-2b (sema-2b) led to the detachment of dendrites from extracellular matrix (ECM) during dendrite outgrowth, resulting in failure of dendrites to be confined in a 2D space. Sema-2b proteins are required in epidermal cells, and act through Plexin-B (PlexB) receptor expressed in the neurons. We further show that Tricornered kinase, target of rapamycin complex 2 (TORC2), and integrins act downstream of the Sema-2b/PlexB signaling. Our findings identify a novel role for semaphorins, which are well-known axon guidance proteins, in regulating dendrite patterning, and several new downstream signaling components of semaphorin signaling.
In chapter 3 we examine the role of easily shocked (eas), which encodes a kinase with a critical role in phospholipid phosphatidylethanolamine (PE) synthesis, in dendrite morphogenesis. eas is required cell-autonomously in da neurons for dendrite growth and stability. Further, we show that the level of Sterol Regulatory Element Binding Protein (SREBP) activity increased in eas mutants, and that decreasing the level of SREBP and its transcriptional targets in eas mutants largely suppressed the dendrite growth defects. Furthermore, reducing Ca2+ influx in neurons of eas mutants ameliorates the dendrite morphogenesis defects. Our study uncovers a novel role for EAS kinase and reveals the in vivo function of phospholipid homeostasis in dendrite morphogenesis.