LTK and ALK promote neuronal polarity and cortical migration by inhibiting IGF1R activity

The establishment of axon‐dendrite polarity is fundamental for radial migration of neurons, cortical patterning, and formation of neuronal circuits. Here, we show that the receptor tyrosine kinases, Ltk and Alk, are required for proper neuronal polarization. In isolated primary mouse embryonic neurons, the loss of Ltk and/or Alk causes a multiple axon phenotype. In mouse embryos and newborn pups, the absence of Ltk and Alk delays neuronal migration and subsequent cortical patterning. In adult cortices, neurons with aberrant neuronal projections are evident and axon tracts in the corpus callosum are disrupted. Mechanistically, we show that the loss of Alk and Ltk increases the cell‐surface expression and activity of the insulin‐like growth factor 1 receptor (Igf‐1r), which activates downstream PI3 kinase signaling to drive the excess axon phenotype. Our data reveal Ltk and Alk as new regulators of neuronal polarity and migration whose disruption results in behavioral abnormalities. Synopsis The receptor tyrosine kinases, LTK and ALK, play key roles in neuronal polarization and cortical patterning by inhibiting cell surface expression and activity of IGF‐1R which, in turn, controls downstream PI3 kinase signaling and axonogenesis. Absence of Ltk/Alk receptors disrupts axon formation, cortical migration and patterning and results in behavioral anomalies in mice. Lack of expression or inhibition of Ltk/Alk increases cell surface expression and activity of the insulin‐like growth factor 1 receptor (Igf‐1r), which leads to activation of PI3K and aberrant axonogenesis. Ligand‐mediated activation of Ltk/Alk promotes phosphorylation and decreases cell‐surface expression and signaling of Igf‐1r, to control neuronal morphology. Graphical Abstract The receptor tyrosine kinases, LTK and ALK, play key roles in neuronal polarization and cortical patterning by inhibiting cell surface expression and activity of IGF‐1R which, in turn, controls downstream PI3 kinase signaling and axonogenesis.