Distinct Roles for EphA7 Isoforms in Cortical Dendritic Elaboration and Synapse Formation

Abstract

The cerebral cortex consists of complex circuitry that directs diverse functions. Development of the cortex relies upon precise coordination between inherent genetic programs and environmental signals to create distinct cell populations with unique functions and connections. A defining aspect of neuronal identity is the size and shape of dendrites, the part of a neuron that receives input, including excitatory signals onto thousands of small protrusions, called dendritic spines. Information conveyed through dendritic arbors and spines impacts neuronal physiology and abnormal development of either structure is associated with neurodevelopmental disorders. Therefore, it is critical to understand molecules responsible for proper dendritic patterning.

This dissertation describes diverse roles for EphA7, an intercellular signaling molecule, in cortical dendritic development. Eph receptors interact with ephrin ligands on adjacent cells to induce changes in neuronal shape and connections. The first part of this work revealed that dendritic avoidance of the ligand ephrin-A5 occurs via EphA7, acting through the Tsc1 and Src signaling pathways. A series of loss- and gain-of-function studies demonstrated that EphA7 controls the overall shape of cortical dendrites by restricting length and branching, while in more mature neurons, EphA7 is required for the formation of functional dendritic spines. Thus, consequences of EphA7 signaling in dendrites shift over time from restricting growth to promoting intercellular contact.

The second part of this work examines the molecular basis for the developmental shift in EphA7 function. In vivo studies demonstrate that dendritic elaboration, but not dendritic spine formation is controlled by EphA7 inhibition of the mTOR growth pathway. We hypothesized that two EphA7 isoforms in cortex might mediate the change in downstream signaling. Expression studies revealed the full-length, kinase-active receptor (FL) is most highly expressed during cortical dendritic elaboration, while a truncated, enzymatically inactive receptor (T1) is expressed highly during dendritic spine formation. Overexpression of FL or T1 results in contrasting effects on dendrite maturation in vitro. Finally, FL and T1 directly interact to modulate downstream signaling. Our results indicate the presence of T1 can modulate FL EphA7 signaling during cortical development, highlighting the importance of structural diversity in Eph receptor signaling during neuronal maturation.