Yeh, ML; (2013) The role of Slit-Robo signalling in the generation of cortical pyramidal neurons. Doctoral thesis , UCL (University College London).

Abstract

The elaborate cytoarchitecture of the mammalian neocortex requires the timely production of its constituent pyramidal neurons and interneurons, and their disposition in appropriate layers. Numerous chemotropic factors present in the forebrain throughout cortical development play important roles in the orchestration of these developmental events. The Roundabout (Robo) family of receptors, together with their ligands, the Slit proteins, are expressed in the developing forebrain, which play important roles in the formation of major axonal tracts and commissures. More recently, Robo1 has been implicated in cortical interneuron proliferation and migration, but few studies have investigated its role in the development of pyramidal neurons. Here, I investigated the functions of Robo and Slit genes in the generation and disposition of pyramidal neurons during cortical formation. I first observed expression of Robo1 and Slit genes (Slit1, Slit2) in cells lining the telencephalic ventricles. I, then, found significant increases in basal progenitor cells at E12.5, and both apical and basal progenitors at E14.5 in the developing cortex of Robo1-/-, Slit1-/- and Slit1-/-/Slit2-/-, but not in mice lacking the other Robo or Slit genes. Further, analysis of Robo1-/-/Robo2-/- double mutants indicated that Robo2 is unlikely to be involved in these proliferative events. Using layer-specific markers, I found that both early and late-born pyramidal neuron populations were significantly increased in the cortices of Robo1-/- mice at the end of corticogenesis (E18.5). The observed increase in pyramidal neurons was likely due to prolonged proliferative activity of progenitors and not to changes in cell cycle events. This finding, confirmed by delivering, through in utero electroporation, Robo1 shRNA or control constructs into apical progenitor cells along the VZ, as well as in dissociated cortical cell cultures, points to a novel role for Robo1 in regulating the proliferation and generation of pyramidal neurons. The excess number of pyramidal neurons generated prenatally appear to die in early postnatal life, but the lamination of the cortex is altered, especially in the upper layers.

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