LTK and ALK regulate neuronal polarity and cortical migration by modulating IGF1R activity

Abstract

AbstractThe establishment of axon-dendrite polarity is fundamental for radial migration of neurons, cortical patterning and formation of neuronal circuitry. Here, we demonstrate that the receptor tyrosine kinases, Ltk and Alk, are required for proper neuronal polarization. In isolated primary mouse embryonic neurons, loss of Ltk and/or Alk yields a striking multiple axon phenotype. In mouse embryos and newborn pups, the absence of Ltk and Alk results in a delay in neuronal migration and subsequent cortical patterning. In adult cortices, neurons with aberrant neuronal projections are evident and there is a disruption of the axon tracts in the corpus callosum. Mechanistically, we show that loss of Alk and Ltk increases cell surface expression and activity of the insulin-like growth factor 1 receptor (Igf-1r), which acts to activate downstream PI3 kinase signalling to drive the excess axon phenotype. Thus, our data reveal Ltk and Alk as new regulators of neuronal polarity and migration whose disruption results in behavioural abnormalities.