The Drosophila NuMA Homolog Mud Regulates Spindle Orientation in Asymmetric Cell Division

Abstract

During asymmetric cell division, the mitotic spindle must be properly oriented to ensure the asymmetric segregation of cell fate determinants into only one of the two daughter cells. In Drosophila neuroblasts, spindle orientation requires heterotrimeric G proteins and the G alpha binding partner Pins, but how the Pins-G alphai complex interacts with the mitotic spindle is unclear. Here, we show that Pins binds directly to the microtubule binding protein Mud, the Drosophila homolog of NuMA. Like NuMA, Mud can bind to microtubules and enhance microtubule polymerization. In the absence of Mud, mitotic spindles in Drosophila neuroblasts fail to align with the polarity axis. This can lead to symmetric segregation of the cell fate determinants Brat and Prospero, resulting in the mis-specification of daughter cell fates and tumor-like over proliferation in the Drosophila nervous system. Our data suggest a model in which asymmetrically localized Pins-G alphai complexes regulate spindle orientation by directly binding to Mud.

Aurora-A acts as a tumor suppressor and regulates self-renewal of Drosophila neuroblasts

“…4AЈЉ) centrosomes can be observed. mud NBs also exhibit spindle orientation and centrosome organization defects (Bowman et al 2006;Izumi et al 2006;Siller et al 2006) similar to those seen for aurA. Mud is required for proper spindle orientation in NBs and it is normally localized to both centrosomes and forms an apical crescent in wild-type NBs (Fig.…”

“…During NB asymmetric divisions, the mitotic spindle is oriented along an axis perpendicular to the epithelial layer and an asymmetric spindle is generated to give rise to two unequal-sized daughter cells with distinct cell fates. NB asymmetric divisions are controlled by an apically localized complex of proteins that include the Drosophila homologs of the conserved Par3 (Bazooka, Baz)/Par6 (DmPar6)/atypical protein kinase C(DaPKC) proteins (Kuchinke et al 1998;Wodarz et al 2000;Petronczki and Knoblich 2001), Inscuteable (Insc) (Kraut et al 1996), and heterotrimeric G proteins G␣i (Schaefer et al 2001;Yu et al 2003) and their regulators Partner of Insc (Pins) (Yu et al 2000), Locomotion defects (Loco) , and a Pins-interacting protein mushroom body defective (Mud) (Bowman et al 2006;Izumi et al 2006;Siller et al 2006). The asymmetric localization of G␣i requires G␤ (Schaefer et al 2001;Yu et al 2003) and G␥ (Fuse et al 2003) and its membrane localization requires Ric-8 (Hampoelz et al 2005;Wang et al 2005).…”

Insights into neural stem cell biology from flies

“…The three proteins are considered to be orthologues, which stimulate microtubule polymerization and bind to Pins proteins (AGS3 in mammalians and GPR proteins in C. elegans). In Drosophila mud mutant, neuroblasts fail to align their mitotic spindle with Pins/Gai cortical polarity (Bowman et al 2006;Izumi et al 2006;Siller et al 2006).…”

Le fuseau mitotique, le centrosome et le cancer : trouvez l’intrus !

“…Lorsque la division cellulaire s'achève, ces déterminants se retrouvent de manière différentielle dans les deux cellules filles. Cette ségrégation inégale des détermi-nants dépend d'une orientation spécifique du fuseau mitotique ( Figure 5A) [30][31][32][33][34][35]. Lors de l'orientation du fuseau mitotique (entrée en mitose), c'est le centrosome le plus âgé qui commence à nucléer les microtubules nécessaires à l'orientation du fuseau mitotique [36].…”