Hernandez-Miranda, L.R.; (2010) Role of Robo1 receptor in semaphorin signalling system and cortical interneuron migration. Doctoral thesis , UCL (University College London).

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Abstract

En route to the cerebral cortex, interneurons encounter the developing striatum and avoid it. It has been shown that these cells express neuropilin (Nrp) as well as PlexinA receptors, which allow these cells to respond to Sema3A and Sema3F chemorepulsive cues expressed in the developing striatum and as consequence they migrate around it and into their proper tangential migratory paths. Robo proteins (receptors for the chemorepulsive family of ligands Slit) have also been observed in cortical interneurons, and they are thought to modulate the morphology of migrating interneurons as well as to play a role in their migration. In the present work, I found that Robo1, but not Robo2 or Slit1/Slit2, deficient (Robo1-/-) mice contain a significant number of cortical interneurons migrating aberrantly through their developing striatum. In vitro experiments showed that dissociated cells taken from the medial ganglionic eminence (MGE, major source of cortical interneurons) of Robo1-/- mice do not respond to either Sema3A or Sema3F induced chemorepulsion. Moreover, I observed significant down regulation of Nrp and PlexinA receptors, as well as reduced levels of Sema3F expression and of some intracellular effectors activated by Sema3A and Sema3F in Robo1-/- cortical interneurons. Using a cell line as an in vitro model, I confirmed that perturbation of Robo1 signalling results in loss of responsiveness to Sema3A and Sema3F, as well as down regulation of their receptors. Additionally, I found that Robo1 can bind directly to Nrp and PlexinA proteins. Taken together, the data presented here suggest a novel role for Robo1 receptor in controlling the expression of distinct components of the class 3 semaphorin signalling system and thus, the migration of cortical interneurons. They also suggest that the migration of cortical interneurons around the striatum might result from the collaborative effort of Robo1receptors and the class 3 semaphorin signalling system.

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