Asymmetric localization of the membrane-associated Numb protein is a primary mechanism for restricting Notch signaling

The development of the external sensory organs in the adult Drosophila notum begins with the formation of sensory organ precursors (SOP) in the wing disc epithelium. The SOP divides along the anteroposterior (AP) axis to produce the IIa and IIb secondary precursors; the posterior IIa cell generates the external socket (tormogen) and hair (trichogen) cells, while the anterior IIb cell gives rise to the internal neuron and sheath (thecogen) cells (Gho et al., 1996; Gho and Schweisguth, 1998; Hartenstein and Posakony, 1989; Wang et al., 1997). Macrochaete SOPs begin dividing around 0-1 hours after pupal formation (APF) and the microchaete SOPs divide at 14-16 hours APF (Hartenstein and Posakony, 1989). A careful orchestration of intrinsic and extrinsic cues is required for the specification of cell fate in the SOP lineage (Campos-Ortega, 1996; Jan and Jan, 1995; Posakony, 1994). Extrinsic signaling is mediated by the Notch pathway, in which Delta or Serrate ligand activates the transmembrane Notch receptor, resulting in nuclear translocation of an intracellular domain of Notch together with the Suppressor of Hairless (SuH) transcription factor (reviewed in Bray, 1998). Loss or reduction of Notch signaling can transform IIa into IIb, socket into hair or sheath cell into neuron; an activated Notch receptor can produce the opposite cell fate transformations for each of these cell types (reviewed in Campos-Ortega, 1996). Thus, regulating Notch activity is essential for establishing distinct sibling cell fates at each division in the SOP lineage. Asymmetric localization of the membrane-associated Numb protein is a primary mechanism for restricting Notch signaling activity to just one of two sibling cells. Numb is segregated into the IIb cell during mitosis (Rhyu et al., 1994) and numb mutants have a transformation of IIb into IIa cell fate that is dependent on Notch function (Guo et al., 1995; Uemura et al., 1989). These results suggest that Numb antagonizes Notch signaling to confer IIb cell fate. A similar relationship of Numb inhibition of Notch signaling also controls hair/socket and neuron/sheath sibling fates at the next step in the SOP lineage (Jan and Jan, 1995; Posakony, 1994) and many or all sibling neuron fates in the CNS (Skeath and Doe, 1998; Spana and Doe, 1996; Spana et al., 1995). The prospero gene encodes a divergent homeodomain transcription factor that is asymmetrically localized in CNS, PNS and non-neural lineages in the embryo (Hirata et al., 1995; Knoblich et al., 1995; Spana and Doe, 1995). In the embryonic CNS, neuroblasts divide asymmetrically to produce smaller ganglion mother cells (GMCs), with each 2063 Development 126, 2063-2071 (1999) Printed in Great Britain © The Company of Biologists Limited 1999 DEV8583