Frank, K; (2015) Wnt signalling in the regulation of spine morphogenesis. Doctoral thesis , UCL (University College London).

Abstract

Excitatory synapses preferentially form onto dendritic spines. Importantly, ab-normal spine morphology and density are associated with several neurological dis-eases. Thus, the appropriate formation of spines is critical for the proper function of neuronal circuits. However, the mechanisms that regulate spinogenesis remain poorly characterized. Recently, our lab demonstrated that Wnt7a stimulates the formation and matura-tion of excitatory synapses by regulating spine morphogenesis. The aim of my thesis was to dissect the mechanisms by which Wnts promote spinogenesis. I found that Wnt7a-mediated spine morphogenesis requires both translation and transcription. Moreover, my studies revealed that Wnt7a activates, through Ca2+/calmodulin-dependent (CaM) kinases, the transcription factor cAMP response element-binding protein (CREB) to induce spinogenesis. Interestingly, Wnt7a in-creases BDNF transcripts suggesting that Wnt7a is upstream of BDNF during neu-ronal circuit formation. Together, my studies demonstrate that Wnt7a induces spino-genesis in a transcription-dependent manner that requires CREB. Neuronal activity is known to modulate spine morphogenesis. However, little is known about molecules regulating activity-mediated spinogenesis. I observed that long-term potentiation (LTP) upregulates transcripts of several Wnt signalling com-ponents. This finding together with previous results indicates that activity-dependent changes in spine morphogenesis might be modulated by Wnt signalling. I also examined the role of microspherule protein 1 (MCRS1), an mRNA-binding protein, in Wnt-mediated spinogenesis to further elucidate the mechanism by which Wnt7a induces spine morphogenesis through translation. I showed that MCRS1 localizes to spines and interacts with Dishevelled-1, a key protein in Wnt signalling. My results suggest that MCRS1 might mediate some aspects of Wnt-mediated spine maturation. In conclusion, my studies demonstrate new roles for Wnt signalling in spinogen-esis. Neuronal activity, which results in LTP, increases mRNA levels of Wnt signal-ling components. Moreover, Wnt7a mediates spine morphogenesis through a CaM kinase-CREB pathway in a similar manner than activity. Collectively, this suggests that LTP-associated spinogenesis is regulated by Wnt signalling.

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