Transcription Factors Sp8 and Sp9 Coordinately Regulate Olfactory Bulb Interneuron Development

Abstract Neural stem cells in the postnatal telencephalic ventricular-subventricular zone (V-SVZ) generate new interneurons, which migrate tangentially through the rostral migratory stream (RMS) into the olfactory bulb (OB). The Sp8 and Sp9 transcription factors are expressed in neuroblasts, as well as in the immature and mature interneurons in the V-SVZ-RMS-OB system. Here we show that Sp8 and Sp9 coordinately regulate OB interneuron development: although Sp9 null mutants show no major OB interneuron defect, conditional deletion of both Sp8 and Sp9 resulted in a much more severe reduction of OB interneuron number than that observed in the Sp8 conditional mutant mice, due to defects in neuronal differentiation, tangential and radial migration, and increased cell death in the V-SVZ-RMS-OB system. RNA-Seq and RNA in situ hybridization reveal that, in Sp8/Sp9 double mutant mice, but not in Sp8 or Sp9 single mutant mice, newly born neuroblasts in the V-SVZ-RMS-OB system fail to express Prokr2 and Tshz1 expression, genes with known roles in promoting OB interneuron differentiation and migration, and that are involved in human Kallmann syndrome.