Abstract
The shape of a neuron facilitates its functionality within neural circuits. Dendrites integrate incoming signals from axons, receiving excitatory input onto small protrusions called dendritic spines. Therefore, understanding dendritic growth and development is fundamental for discerning neural function. We previously demonstrated that EphA7 receptor signaling during cortical development impacts dendrites in two ways: EphA7 restricts dendritic growth early and promotes dendritic spine formation later. Here, the molecular basis for this shift in EphA7 function is defined. Expression analyses reveal that EphA7 full-length (EphA7-FL) and truncated (EphA7-T1; lacking kinase domain) isoforms are dynamically expressed in the developing cortex. Peak expression of EphA7-FL overlaps with dendritic elaboration around birth, while highest expression of EphA7-T1 coincides with dendritic spine formation in early postnatal life. 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 shifts during development, such that in vivo inhibition of mTOR by rapamycin in EphA7-mutant neurons ameliorates dendritic branching, but not dendritic spine phenotypes. Finally, direct interaction between EphA7-FL and EphA7-T1 is demonstrated in cultured cells, which results in reduction of EphA7-FL phosphorylation. In cortex, both isoforms are colocalized to synaptic fractions and both transcripts are expressed together within individual neurons, supporting a model where EphA7-T1 modulates EphA7-FL repulsive signaling during development. Thus, the divergent functions of EphA7 during cortical dendrite development are explained by the presence of two variants of the receptor.
Highlights
In the cerebral cortex, diverse neuronal populations are arranged and this organization underlies remarkable functional complexity [1,2,3,4]
Cortical neurons in mutant mice lacking all EphA7 isoforms (EphA7-/-) have longer, more complex dendrites and fewer excitatory synapses compared to cortical neurons in wild type (WT) mice [25]
To understand the developmental expression of EphA7-FL and EphA7-T1 in cortex, semi-quantitative RT-PCR was performed using isoform-specific primers and values were averaged across 3 animals or 3 culture preparations per time point
Summary
Diverse neuronal populations are arranged and this organization underlies remarkable functional complexity [1,2,3,4]. Newly differentiated, bipolar-shaped neurons begin to migrate toward the cortical plate, with a leading process that draws the cell toward the pial surface and a trailing process that extends toward the ventricle [7,8,9]. This polarity sets the stage for the eventual maturation of the neuron, which is guided by intrinsic and extrinsic programs [reviewed in 6,10]. The trailing process becomes the axon and the leading process develops into the apical dendrite, which will retract or branch extensively, depending on the cell type. Despite recognition that dendritic form is critical to neuronal function, mechanisms guiding dendrite development remain obscure
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