Abstract
During cortical development, neurons undergo polarization, oriented migration and layer-type differentiation. The biological and biochemical mechanisms underlying these processes are not completely understood. In neurons in culture we showed that IGF-1 receptor activation is important for growth cone assembly and axonal formation. However, the possible roles of the insulin like growth factor-1 receptor (IGF-1R) on neuronal differentiation and polarization in vivo in mammals have not yet been studied. Using in utero electroporation, we show here that the IGF-1R is essential for neocortical development. Neurons electroporated with a shRNA targeting IGF-1 receptor failed to migrate to the upper cortical layers and accumulated at the ventricular/subventricular zones. Co-electroporation with a constitutively active form of PI3K rescued migration. The change of the morphology from multipolar to bipolar cells was also attenuated. Cells lacking the IGF-1 receptor remain arrested as multipolar forming a highly disorganized tissue. The typical orientation of the migrating neurons with the Golgi complex oriented toward the cortical upper layers was also affected by electroporation with shRNA targeting IGF-1 receptor. Finally, cells electroporated with the shRNA targeting IGF-1 receptor were unable to form an axon and, therefore, neuron polarity was absent.
Highlights
The vertebrate cortex is responsible for the high cognitive functions of the brain
In this work we provide evidence indicating that early expression of insulin like growth factor-1 receptor (IGF-1R) could be required for the normal orientation of cortical neuron precursors, with the Golgi complex oriented toward the cortical plate[22]
After a polarity switch from multipolar to bipolar, they extend an axon at the upper IZ3, 4, 19, 20.This polarity switch is an important step during radial migration that has been implicated in specification of neuron subtype identity, cortical lamination, and projection formation[3, 9, 23,24,25]
Summary
The vertebrate cortex is responsible for the high cognitive functions of the brain. It is organized into distinct layers of neurons and within each layer neurons share similar functions, morphology and birthdates[1]. Most cortical pyramidal projecting neurons originate from asymmetric division of radial glia progenitors in the ventricular zone They migrate radially towards the marginal zone and through the subventricular zone (SVZ) and lower intermediate zone. The cells reorient their centrosomes and Golgi toward the pial surface, as they move to the upper part of the intermediate zone[5] Their morphology changes from multipolar to bipolar and they resume radial migration[6]. Phosphatidylinositol-3 kinase (PI3K) is activated and its product, PIP3, accumulates in the distal region of the neurite, together with IGF-1R These events are critical for the outgrowth of the future axons and the establishment of neuronal polarity[10,11,12].
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