Semaphorin3A-neuropilin1 signalling is involved in the generation of cortical interneurons

Cortical interneurons are generated predominantly in the medial ganglionic eminence of the ventral telencephalon and migrate to the cortex during embryonic development. These cells express neuropilin (Nrp1 and Nrp2) receptors which mediate their response to the chemorepulsive class 3 semaphorin (Sema) ligands. We show here that semaphorins Sema3A and Sema3F are expressed in layers adjacent to cortical interneuron migratory streams as well as in the striatum, suggesting they may have a role in guiding these cells throughout their journey. Analysis of Sema3A ^-/- and Sema3F ^-/- mice during corticogenesis showed that absence of Sema3A, but not Sema3F, leads to aberrant migration of cortical interneurons through the striatum. Reduced number of cortical interneurons was found in the cortex of Sema3A ^-/-, Nrp1 ^-/- and Nrp2 ^-/- mice, as well as altered distribution in Sema3F ^-/-, Nrp1 ^-/-, Nrp2 ^-/- animals and especially in neuropilin double mutants. The observed decrease in interneurons in Sema3A ^-/- and Nrp1 ^-/- mice was due to altered proliferative activity of their progenitors highlighted by changes in their mitotic spindle positioning and angle of cleavage plane during cell division. These findings point to a novel role for Sema3A-Nrp1 signalling in progenitor cell dynamics and in the generation of interneurons in the ventral telencephalon.