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bioRxiv · 10.1101/2020.03.27.011486

EphA7 Isoforms Differentially Regulate Cortical Dendrite Development

Leonard, C. E.·Baydyuk, M.·Stepler, M. A.·Burton, D. A.·Donoghue, M. J.
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Abstract

The shape of a neuron reflects its cellular function and ultimately, how it operates in neural circuits. Dendrites receive and integrate incoming signals, including excitatory input onto dendritic spines, so understanding how dendritic development proceeds is fundamental for discerning neural function. Using loss- and gain-of-function paradigms, we previously demonstrated that EphA7 receptor signaling during cortical development impacts dendrites in two ways: restricting growth early and promoting spine formation later. Here, the molecular basis for this shift in EphA7 function is defined. Expression analyses reveal that both full-length (EphA7-FL) and truncated (EphA7-T1; lacking kinase domain) isoforms of EphA7 are expressed in the developing cortex, with peak expression of EphA7-FL overlapping with dendritic elaboration and highest levels of EphA7-T1 coinciding with spine formation. Overexpression studies in cultured neurons demonstrate that EphA7-FL inhibits both dendritic growth and spine formation, while EphA7-T1 increases spine density. Furthermore, signaling downstream of EphA7 varies during development; in vivo inhibition of kinase-dependent mTOR by rapamycin in EphA7 mutant neurons rescues the dendritic branching, but not the dendritic spine phenotypes. Finally, interaction and signaling modulation was examined. In cells in culture, direct interaction between EphA7-FL and EphA7-T1 is demonstrated which results in EphA7- T1-based modulation of EphA7-FL phosphorylation. In vivo, both isoforms are colocalized to cortical synapses and levels of phosphorylated EphA7-FL decrease as EphA7-T1 levels rise. Thus, the phenotypes of EphA7 during cortical dendrite development are explained by divergent functions of two variants of the receptor.

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Leonard, C. E., Baydyuk, M., Stepler, M. A., Burton, D. A., Donoghue, M. J.. 2020-03-27. EphA7 Isoforms Differentially Regulate Cortical Dendrite Development. https://doi.org/10.1101/2020.03.27.011486

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