NEURONAL POLARITY

Pyramidal neuron polarity decisions during migration and axonal outgrowth in the developing mammalian cerebral cortex

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 Obiettivo del progetto (Objective)

'During embryonic brain development, pyramidal projection neurons are born in the ventricular zone and migrate radially towards the upper part of the cortex to form the cortical plate. These neurons also have to develop dendrites and axons in order to make connections. Several brain diseases and mental illness derive from defects in neuronal migration and positioning or in axon-target interactions for the establishment of synaptic circuitry. Studies with cultured pyramidal neurons have shown that similar polarity decisions, and many of the same proteins, specify the direction of migration and the orientation of axon outgrowth. However, in vivo, in developing brain, it appears that axons start growing before the completion of neuronal migration, and the axon is always positioned at the opposite side to the migration front. An important open question is to understand how the neuron is able to distinguish spatially and temporally these two opposite polarity signals by using the same polarity proteins in vivo. The results suggest that the situation in a polarized epithelium in vivo is different to that observed in vitro. Indeed, in non-mammalian organism such as the fly, some polarity proteins seem to be dispensable for polarized neuronal migration. We propose to determine the position of the apical pole of a pyramidal neuron during its migration and differentiation in vivo during mouse brain development. We will identify the timing of possible switches in cell polarity relative to the timing of axon emergence, and identify molecules involved in these decisions. Importantly, our studies will be done in vivo and in a living brain slice culture assay.'

Introduzione (Teaser)

One of the marvels of brain development is the mass migration of nerve cells to their functional position. European research has investigated the molecules required for their successful navigation.

Descrizione progetto (Article)

Formation of the cerebral cortex during embryonic development requires the migration of billions of cells from their birth position to their final destination. A motile nerve cell must have internal polarity to move in the specified direction. What is more, neurons then have to extend neurites or projections from the cell body to communicate with each other.

The key to this extraordinary feat of organisation lies in cell signalling pathways. The EU-funded Neuronal Polarity project aimed to characterise these cascades important in cerebral cortex development. At a later stage, defective cortical architecture can be responsible for brain pathologies including microcephaly, epilepsy and schizophrenia.

Project scientists showed that in vivo the guanine triphosphatase GTPase Ras-proximate-1 (Rap 1) caused an accumulation of neurons halfway to their destination. The team used time-lapse video microscopy and immunostaining to show that the problem does not lie with motility of the neurons but in a defect in their polarity. Other evidence from motility tests in vitro and the fact that some neurons do actually make it to their destination, albeit slowly, suggest Rap 1 is important for initial polarisation of the neurons.

The transmembrane receptor N-cadherin (Ncad) also has an important function in polarising cortical neurons. Experimental data confirmed that this receptor is involved downstream from Rap 1. Overall, inhibition of Rap 1 reduces Ncad presence.

Neuronal Polarity scientists suggest that Rap 1 activity is important in migrating neurons to maintain a high level of Ncad at the plasma membrane for nerve cells to polarise correctly.

Exactly how Ncad interacts with molecular cascades for neuron polarisation is still under investigation. The Neuronal Polarity project accumulated data on which to base a concrete research path for future investigation.