Parallel Activin and BMP signaling coordinates R7/R8 photoreceptor subtype pairing in the stochastic Drosophila retina

Abstract

Drosophila color vision is achieved by comparing outputs from two types of color-sensitive photoreceptors, R7 and R8. Ommatidia (unit eyes) are classified into two subtypes, known as ‘pale’ or ‘yellow’, depending on Rhodopsin expression in R7 and R8. Subtype specification is controlled by a stochastic decision in R7 and instructed to the underlying R8. We find that the Activin receptor Baboon is required in R8 to receive non-redundant signaling from the three Activin ligands, activating the transcription factor dSmad2. Concomitantly, two BMP ligands activate their receptor, Thickveins, and the transcriptional effector, Mad. The Amon TGFβ processing factor appears to regulate components of the TGFβ pathway specifically in pale R7. Mad and dSmad2 cooperate to modulate the Hippo pathway kinase Warts and the growth regulator Melted; two opposing factors of a bi-stable loop regulating R8 Rhodopsin expression. Therefore, TGFβ and growth pathways interact in postmitotic cells to precisely coordinate cell-specific output.

Coordination between stochastic and deterministic specification in the Drosophila visual system

“…In Drosophila, patterning of the mosaic of ommatidial subtypes is established by sequential steps and is initiated in R7 photoreceptors by a single transcription factor, Ss. This initial decision is then transmitted to the R8 of the same ommatidium so that R7 and R8 have paired Rhodopsins expression (Wells et al, 2017). In contrast, we show here that the mechanism responsible for the coordination of R7 subtype specification with their main post-synaptic target in the brain is different.…”

“…Two alternative mechanisms could allow this matching: (i) R7 subtypes could directly coordinate their fate with their Dm8 subtypes by instructing naïve Dm8s during development to adopt the appropriate fate (p vs. y). This would be similar to the coordination between R7 and R8 fates where pR7s signal to R8s within the same ommatidium and instruct them to adopt the pR8 fate (Wells et al, 2017). (ii) Alternatively, distinct Dm8s subtypes could be specified independently of R7 subtypes, such that matching would occur during later stages in development.…”

“…Once this decision is made cell autonomously by R7, it is propagated to R8 in the same ommatidium so that R7 and R8 have coupled Rhodopsin expression. This is achieved through induction of the pR8 fate by pR7s through Activin and BMP signaling while the yR8 fate is specified by default (Mikeladze-Dvali et al, 2005;Wells et al, 2017). R7 and R8 send their axons to the medulla, the second neuropile of the optic lobe where they make synapses with some of the ∼40,000 neurons of more than 80 different cell types that compose the medulla ( Figure 1C) (Fischbach and Dittrich, 1989;Konstantinides et al, 2018).…”

Identification of genes involved in the differentiation of R7y and R7p photoreceptor cells inDrosophila

“…Interestingly, the interaction network defined by the candidate genes contains several genes previously shown to influence specification of Rh3 or Rh4 expression in R7 photoreceptor cells (Rh3%) as well as the inductive signal that is thought to coordinate the expression of opsin genes in adjacent R7 and R8 photoreceptor cells within individual ommatidia. These include (Egfr) (BIRKHOLZ et al 2009) that is required in both processes, as well as Merlin (Mer), wts, hpo, kibra yki (JUKAM AND DESPLAN 2011;JUKAM et al 2013) and thickveins (tkv) (WELLS et al 2017) that coordinate opsin gene expression in R7 and R8 cells. Furthermore, one of the candidate genes identified in the screen, Fur2, has also been shown to regulate the induction of Rh5 expression in R8 cells (WELLS et al 2017).…”

“…These include (Egfr) (BIRKHOLZ et al 2009) that is required in both processes, as well as Merlin (Mer), wts, hpo, kibra yki (JUKAM AND DESPLAN 2011;JUKAM et al 2013) and thickveins (tkv) (WELLS et al 2017) that coordinate opsin gene expression in R7 and R8 cells. Furthermore, one of the candidate genes identified in the screen, Fur2, has also been shown to regulate the induction of Rh5 expression in R8 cells (WELLS et al 2017). These results suggest numerous mechanisms through which processes in the R7 cell responsible for R7y versus R7p cell fate may couple to inductive signaling that specifies paired R8y and R8p cell fates.…”