Multiple Signalling Pathways Establish Cell Fate and Cell Number in Drosophila Malpighian Tubules

Abstract

A unique cell, the tip mother cell, arises in the primordium of each Drosophila Malpighian tubule by lateral inhibition within a cluster of achaete-expressing cells. This cell maintains achaete expression and divides to produce daughters of equivalent potential, of which only one, the tip cell, adopts the primary fate and continues to express achaete, while in the other, the sibling cell, achaete expression is lost (M. Hoch et al., 1994, Development 120, 3439-3450). In this paper we chart the mechanisms by which achaete expression is differentially maintained in the tip cell lineage to stabilise cell fate. First, wingless is required to maintain the expression of achaete in the tubule primordium so that wingless mutants lack tip cells. Conversely, increasing wingless expression results in the persistence of achaete expression in the cell cluster. Second, Notch signalling is restricted by the asymmetric segregation of Numb, as the tip mother cell divides, so that achaete expression is maintained only in the tip cell. In embryos mutant for Notch tip cells segregate at the expense of sibling cells, whereas in numb neither daughter cell adopts the tip cell fate resulting in tubules with two sibling cells. Conversely, when numb is overexpressed two tip cells segregate and tubules have no sibling cells. Analysis of cell proliferation in the developing tubules of embryos lacking Wingless after the critical period for tip cell allocation reveals an additional requirement for wingless for the promotion of cell division. In contrast, alteration in the expression of numb has no effect on the final tubule cell number.

Mouse numb is an essential gene involved in cortical neurogenesis

“…For example, asymmetric segregation of d-Numb protein is required for muscle progenitor cells to divide asymmetrically to generate distinct muscle founders (36,37). Asymmetric d-Numb segregation is also necessary during Malpighian tubule development for the tip mother cell to generate two distinct daughter cells, a tip cell and a sibling cell (38). As in Drosophila, m-numb is expressed in many tissues during mouse embryogenesis and likely plays important roles in cell fate specification outside of the nervous system, as indicated by the extensive bleeding and abnormally small size of the mutant embryo.…”

Regulation of vascular morphogenesis by Notch signaling

“…Lateral inhibition through Notch activation restricts the expression of the transcriptional regulators krüppel and achaete to the tip cell. Accordingly, tip cells are absent after ectopic expression of the Notch intracellular domain throughout the developing Malpighian tubules (Hoch et al 1994;Wan et al 2000).…”

Wnt/Notch signalling and information processing during development

“…It is highly unlikely that biological signal transduction is immune to noise. REVIEW Development 135 (3) obvious only in the context of other transcriptional effectors, to the point that its function appears to be to modulate their effects and activities (Baylies et al, 1995;Collins and Treisman, 2000;Cox and Baylies, 2005;Lowry et al, 2005;McGrew et al, 1997;Megason and McMahon, 2002;Wan et al, 2000) …”