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Graduate Program in Neuroscience
BS, 2001 Tsinghua University, China
Thesis Advisor: James Q. Zheng, PhD
Monday, June 9, 2008
Projection of developing axons over long distances to their appropriate targets is required for proper wiring and functioning of the intricate nervous system. In vivo, a variety of extracellular cues are present in a spatially and temporally regulated pattern to provide directional instructions to elongating axons, guiding them to appropriate targets. Ca2+ is an important second messenger that has been demonstrated to mediate the bi-directional growth cone responses, but downstream mechanisms remains largely unknown. Therefore, the focus of my thesis project is to understand how different turning responses are generated by distinct Ca2+ signals.
By using direct focal elevation of [Ca] through photolysis of caged Ca2+, I demonstrated that Ca2+-calmodulin-dependent kinase II (CaMKII) and calcineurin (CaN)-phosphatase-1 (PP1) act as downstream targets of Ca2+ signals to mediate attraction and repulsion, respectively. Significantly, CaMKII/CaN-PP1 acts as a bimodal switch to control the direction of growth cone turning in response to different Ca2+ signals (local and global) by preferentially activating one component over the other. A moderate local Ca2+ elevation preferentially activates CaMKII to induce attraction while a small local Ca2+ signal predominately acts through CaN and phosphatase-1 (PP1) to produce repulsion. Importantly, the resting level of [Ca2+]I at the growth cone directly influences the switch operation as it biases the local Ca2+ signal for differential activation of CaMKII and CaN: a normal baseline allows distinct turning responses to different local Ca2+ signals, while a low baseline favors CaN-PP1 activation for repulsion. Significantly, cAMP-pathway acts as a negative feedback, which negatively regulates the CaN-PP1 side of the switch to modulate growth cone responses.
I further identified that Src kinase and focal adhesion kinase (FAK) act as the downstream effectors of Ca2+ signals to mediate Ca2+ dependent bi-directional growth cone turning responses. Importantly, serine phosphorylation of FAK at S732, which can be induced by Ca2+ signals through CaMKII, is required for Ca2+ dependent growth cone turning mediated by BDNF. Finally, I demonstrated that phosphorylation of ZBP1 at Y396 plays an essential role for BDNF-induced growth cone attraction, which has been shown to act as downstream of Src kinase to promote beta-actin local translation upon BDNF stimulation.
Taken together, these findings provide significant insights towards the downstream mechanisms underlying various turning behaviors induced by complex Ca2+ signals, and demonstrate that Src kinase/FAK play a key role in transducing Ca2+ signals to control Ca2+ dependent growth cone guidance.