Asymmetric Notch activation specifies photoreceptors R3 and R4 and planar polarity in the Drosophila eye

Abstract

Planar polarity is seen in epidermally derived structures throughout the animal kingdom. In the Drosophila eye, planar polarity is reflected in the mirror-symmetric arrangement of ommatidia (eye units) across the dorsoventral midline or equator; ommatidia on the dorsal and ventral sides of the equator exhibit opposite chirality. Photoreceptors R3 and R4 are essential in the establishment of the polarity of ommatidia. The R3 cell is thought to receive the polarizing signal, through the receptor Frizzled (Fz), before or at higher levels then the R4 cell, generating a difference between neighbouring R3 and R4 cells. Both loss-of-function and overexpression of Fz in the R3/R4 pair result in polarity defects and loss of mirror-image symmetry. Here we identify Notch and Delta (Dl) as dominant enhancers of the phenotypes produced by overexpression of fz and dishevelled (dsh), which encodes a signalling component downstream of Fz, and we show that D1-mediated activation of Notch is required for establishment of ommatidial polarity. Whereas fz signalling is required to specify R3, Notch signalling induces the R4 fate. Our data indicate that Dl is a transcriptional target of Fz/Dsh signalling in R3, and activates Notch in the neighbouring R4 precursor. This two-tiered mechanism explains how small differences in the level and/or timing of Fz activation reliably generate a binary cell-fate decision, leading to specification of R3 and R4 and ommatidial chirality.

Signal integration during development: Insights from the Drosophila eye

“…A different protein, the nuclear hormone receptor Seven-up (Svp), appears necessary to maintain R3 and R4 (Mlodzik et al, 1990), but is not expressed in undifferentiated cells and, therefore, is unlikely to be a critical determinant for R3 and R4 fates. It is known that signaling through the transmembrane receptor Frizzled lies upstream of Notch pathway signaling between R3 and R4, but these events occur after the R3/R4 fates have already been specified (Fanto et al, 1998;Fanto and Mlodzik, 1999). Perhaps the only source of R3/R4 specificity is the presentation of secreted Spitz by R2 and R5.…”

Bases génétiques de la polarité planaire

“…Cette inhibition pourrait être relayée par Dishevelled car Dishevelled se lie à la partie intracellulaire de Notch et interfère avec l'activité de signalisation du récepteur Notch. Ainsi, une différence faible et relative d'activité Frizzled introduirait un biais spatial dans la décision R3/R4 [20][21][22]. Inversement, Strabismus et Prickle agiraient dans la cellule polaire pour stimuler l'activité de signalisation de Notch [21].…”

Ral inhibits ligand-independent Notch signaling in Drosophila

“…Frizzled signaling leads to elevated transcription in pre-R3 of the ligand Delta and also the Ubiquitinligase Neuralized. 28,31 Neuralized ubiquitylates Delta, a prerequisite for Delta endocytosis by pre-R3 and activation of Notch in pre-R4. 27 Alternatively or in addition, activated Frizzled relocalizes in a complex with a cortical protein called Disheveled to the R3/R4 interface where the complex prevents Notch receptor activation directly in pre-R3.…”

“…1). [28][29][30] Although each R3/R4 precursor expresses both Notch and the ligand Delta, Notch activation is asymmetric in R3/R4. Because it is closer to the equator, the pre-R3 cell experiences more Frizzled activation and thus activates Notch in the adjacent pre-R4 cell.…”