(A) Overview of Drosophila ESO development. The SOP (pI) cell undergoes a Notch-dependent asymmetric division to create two daughter cells, pIIa and pIIb. The Notch inhibitor, Numb, is asymmetrically distributed between the two daughter cells; thus, the pIIa cell (lower levels of Numb) results from the induction of Notch signaling, and the pIIb cell (higher levels of Numb) results from lower Notch signaling (i.e., the default state in the absence of Notch induction). Loss of Notch during pI differentiation results in the bald (or bristle loss) phenotype, due to the inability of the pI cell to form the external cuticular structures. Each of the pII cells then undergoes a subsequent, Notch-dependent round of asymmetric division. pIIa divides first, to give rise to the bristle and socket cells. pIIb then divides, to give rise to the sensory neuron and sheath cell. Loss of Notch signaling in the pIIa division results in duplication of the bristle cell, whereas loss of Notch signaling in the pIIb division results in two neurons. The reciprocal phenotypes are produced in Notch gain-of-function mutants. The four cells of the ESO, which results from 3 successive asymmetric divisions, are also depicted. This model is greatly simplified and does not include the multiple proteins that modify the outcome of Notch signaling. (B) As reported by Karbowniczek et al. (9), loss of TSC or Rheb activation in the pI (SOP) cell resulted in loss of the pIIb progeny and duplication of the pIIa progeny, with the resultant double bristle (twinning) phenotype. This phenotype is similar to that of Notch gain-of-function mutants. Interestingly, the phenotypic change occurred despite asymmetric distribution of Numb, which raises the question of how Notch signaling is induced in this cell.