Proneural enhancement by Notch overcomes Suppressor-of-Hairless repressor function in the developing Drosophila eye

Background: The receptor protein Notch plays a conserved role in restrictin g neural-fate specification during lateral inhibition. Lateral inhibition r equires the Notch intracellular domain to coactivate Su(H)mediated transcri ption of the Enhancer-of-split Complex. During Drosophila eye development, Notch plays an additional role in promoting neural fate independently of Su (H) and E(spl)-C, and this finding suggests an alternative mechanism of Not ch signal transduction. Results: We used genetic mosaics to analyze the proneural enhancement pathw ay, As in lateral inhibition, the metalloprotease Kuzbanian, the EGF repeat 12 region of the Notch extracellular domain, Presenilin, and the Notch int racellular domain were required. By contrast, proneural enhancement became constitutive in the absence of Su(H), and this led to premature differentia tion and upregulation of the Atonal and Senseless proteins. Ectopic Notch s ignaling by Delta expression ahead of the morphogenetic furrow also caused premature differentiation. Conclusions: Proneural enhancement and lateral inhibition use similar ligan d binding and receptor processing but differ in the nuclear role of Su(H). Prior to Notch signaling, Su(H) represses neural development directly, not indirectly through E(spl)-C. During proneural enhancement, the Notch intrac ellular domain overcomes the repression of neural differentiation. Later, l ateral inhibition restores the repression of neural development by a differ ent mechanism, requiring E(spl)-C transcription. Thus, Notch restricts neur ogenesis temporally to a narrow time interval between two modes of repressi on. (C) 2001 Elsevier Science Ltd. All rights reserved.