Determination of cell fates in the R7 equivalence group of the Drosophila eye by the concerted regulation of D-Pax2 and TTK88

Abstract

In the developing Drosophila eye, the precursors of the neuronal photoreceptor cells R1/R6/R7 and non-neuronal cone cells share the same developmental potential and constitute the R7 equivalence group. It is not clear how cells of this group elaborate their distinct fates. Here we show that both TTK88 and D-Pax2 play decisive roles in cone cell development and act in concert to transform developing R1/R6/R7 into cone cells: while TTK88 blocks neuronal development, D-Pax2 promotes cone cell specification. In addition, ectopic TTK88 in R cells induces apoptosis, which is suppressed by ectopic D-Pax2. We further demonstrate that Phyllopod (Phyl), previously shown to promote the neuronal fate in R1/R6/R7 by targeting TTK for degradation, also inhibits D-Pax2 transcription to prevent cone cell specification. Thus, the fates of R1/R6/R7 and cone cells are determined by a dual mechanism that coordinately activates one fate while inhibiting the other.

Unkempt Is Negatively Regulated by mTOR and Uncouples Neuronal Differentiation from Growth Control

“…hdc and Tsc1 mutant clones also cause a similar increase in D-Pax2 expression. Overexpression of D-Pax2 alone is insufficient to induce cone cell differentiation, which requires overexpression of both D-Pax2 and Tramtrack88 (TTK88) [39]. Thus, regulation of D-Pax2 expression by mTOR signalling may contribute to the rate of cone cell differentiation, while overall control would require the regulation of additional factors such as TTK88 (Figure 8).…”

Structural Rules and Complex Regulatory Circuitry Constrain Expression of a Notch- and EGFR-Regulated Eye Enhancer

“…However, we did not identify putative seven-up binding sites within spa . Phyllopod, an E3 ubiquitin ligase component, represses dPax2 and the cone cell fate in R1/R6/R7, but the transcription factor mediating this effect is not yet known (Shi and Noll, 2009). Perhaps the best candidate for a photoreceptor-specific direct repressor of spa is Bar , which encodes the closely related and redundant homeodomain TFs BarH1 and BarH2.…”

“…We chose to study the sparkling (spa) enhancer of the dPax2 gene, which is necessary and sufficient to specify the cone cell fate in certain multipotent cells in the developing Drosophila eye (Fu and Noll, 1997; Fu et al, 1998; Flores et al, 2000; Shi and Noll, 2009). spa drives cone cell-specific dPax2 expression in response to four direct regulators, acting through twelve transcription factor binding sites (TFBSs): Suppressor of Hairless [Su(H)], under the control of Notch signaling; two Ets factors, the activator PointedP2 (Pnt) and the repressor Yan, both controlled by EGFR/Ras/MAPK signaling; and the Runx-family protein Lozenge (Lz) (Fu et al, 1998; Flores et al, 2000; Tsuda et al, 2002) (Figure 1A).…”

“…In their report describing the direct regulation of the spa enhancer by Su(H), Lz, and Ets factors, Flores et al (2000) proposed a model in which a combinatorial code, Lz + EGFR/Pnt/Yan + Notch/Su(H), determines the cell type specificity of spa activity. The authors were careful to state that “the model…reflects requirements rather than sufficiency for cell fate specification.” Despite this caveat, the Lz+Ets+Su(H) code is now considered to “define the combinatorial input required for cone cell specification” (Voas and Rebay, 2004; see also Pickup et al, 2009; Shi and Noll, 2009). …”

Modeling bistable cell-fate choices in theDrosophilaeye: qualitative and quantitative perspectives

“…7C). Reasonable candidates for these factors include BarH1 and Seven-up (Svp) for R1/6 (Mlodzik et al, 1990;Higashijima et al, 1992;Hiromi et al, 1993;Hayashi et al, 1998;Miller et al, 2008); Spalt major (Salm), Phyllopod (Phyl), Seven in absentia (Sina) and Prospero (Pros) for R7 (Li et al, 1997;Xu et al, 2000;Cook et al, 2003;Domingos et al, 2004;Hayashi et al, 2008); and Pax2 (ShavenFlyBase), Tramtrack (Ttk) and Cut for cone cells (Canon and Banerjee, 2003;Shi and Noll, 2009). Each relationship between cell-fate determinants in the model can be thought of as a separate bistable switch.…”