RNA-binding protein Orb2 causes microcephaly and supports centrosome asymmetry in Drosophila neural stem cells

Abstract

To maintain a balance of self-renewal versus neurogenesis, neural stem cells (NSCs) undergo asymmetric cell division along an invariant polarity axis instructed by centrosomes. In the NSCs of the third instar Drosophila larval brain, the interphase centrosomes are defined by marked asymmetries in protein composition and functional activity as microtubule-organizing centers. Here we show that a conserved RNA-binding protein, Orb2, supports NSC centrosome asymmetry by localizing to the cytoplasm, where it promotes robust apical centrosome maturation and transient basal centrosome inactivation, required for centrosome segregation and spindle morphogenesis. Orb2 is required cell autonomously within NSCs to support centrosome asymmetry and maintenance of the stem cell pool. We suggest Orb2 plays opposing roles in centrosome activation and inactivation at the apical versus basal centrosomes respectively, possibly through the translational regulation of multiple mRNAs. Conversely, loss of orb2 manifests in microcephaly independent of Orb2 function in NSCs. Bioinformatics uncovers a significant overlap among RNA targets between Drosophila Orb2 and human CPEB4, consistent with a conserved role for CPEB proteins in centrosome regulation and neurodevelopment.