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Calcium Signaling in Axon Guidance

by
Zhexing Wen
Graduate Program in Neuroscience

BS, 2001 Tsinghua University, China

Thesis Advisor: James Q. Zheng, PhD


CABM 010

Monday, June 9, 2008
10:00 am


Abstract

Abstract

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.


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