Unequal Segregation of Neuralized Biases Notch Activation during Asymmetric Cell Division

Abstract

In Drosophila, Notch signaling regulates binary fate decisions at each asymmetric division in sensory organ lineages. Following division of the sensory organ precursor cell (pI), Notch is activated in one daughter cell (pIIa) and inhibited in the other (pIIb). We report that the E3 ubiquitin ligase Neuralized localizes asymmetrically in the dividing pI cell and unequally segregates into the pIIb cell, like the Notch inhibitor Numb. Furthermore, Neuralized upregulates endocytosis of the Notch ligand Delta in the pIIb cell and acts in the pIIb cell to promote activation of Notch in the pIIa cell. Thus, Neuralized is a conserved regulator of Notch signaling that acts as a cell fate determinant. Polarization of the pI cell directs the unequal segregation of both Neuralized and Numb. We propose that coordinated upregulation of ligand activity by Neuralized and inhibition of receptor activity by Numb results in a robust bias in Notch signaling.

Genome Engineering-Based Analysis of Bearded Family Genes Reveals Both Functional Redundancy and a Nonessential Function in Lateral Inhibition in Drosophila

“…While previous clonal studies have indicated that neur is required for lateral inhibition (Yeh et al 2000;Le Borgne and Schweisguth 2003), the influence of neur gene dosage on sensory cell fate has not been studied. A role for Neur during competition is not necessarily expected since neur transcripts and Neur proteins have been detected in SOPs but not in PNC cells (Boulianne et al 1991;Le Borgne and Schweisguth 2003). Indeed, this expression pattern suggests that neur may only act in singled out SOPs to reinforce lateral signaling and that it does not act when PNC cells still compete for the SOP fate.…”

“…The activity of Dl is positively regulated at the posttranscriptional level by the E3 ubiquitin ligase Neuralized (Neur) and Neur-dependent Dl signaling is essential for proper SOP specification (Boulianne et al 1991;Lai et al 2001;Pavlopoulos et al 2001;Le Borgne and Schweisguth 2003;Le Borgne et al 2005). Recent studies have shown that regulation of Dl activity by Neur is antagonized by proteins of the Bearded (Brd) family.…”

Cell and molecular biology of Notch

“…Furthermore analysis of zebrafish mutants uncovered Mind bomb as an ubiquitin ligase required for Delta endocytosis and this was followed by the observation of similar proteins in Drosophila (Neuralized and D-Mind bomb 1 and 2). These proteins act on Delta to promote ubiquitination and endocytosis and thus enhance the signalling ability of the signal-sending cells (Pavlopoulos et al 2001, Le Borgne & Schweisguth 2003, Itoh et al 2003, Lai et al 2005, Bardin & Schweisguth 2006. Ubiquitination of the DSL ligands makes them targets of adaptor proteins such as liquid facets (Lqf, a homologue for epsin) which promotes endocytosis (Wang & Struhl 2004.…”

“…The best characterized function of Notch is probably 'lateral inhibition', a process of central importance in the assignation of cell fates and their spatial patterning (Heitzler & Simpson 1993, Le Borgne & Schweisguth 2003, Gibert & Simpson 2003. The notion of lateral inhibition is derived from the observation that during development, groups of cells emerge that are assigned a common developmental potential but only some cells within the group adopt that potential.…”

“…Asymmetric distribution of regulators of Notch signalling activity determines the identity of the daughter cells as signalsending or signal-receiving cell. Once Notch signalling is elicited, the cells differentiate according to binary cell fate decision mediated by Notch (Frise et al 1996, Le Borgne & Schweisguth 2003, Hutterer & Knoblich 2005. This asymmetric distribution of Notch regulators in neurogenesis is regulated by polarity proteins such as Bazooka, PAR-6, DaPKC, Inscuteable and Partner of Inscuteable (Schober et al 1999, Wodarz et al 1999.…”