Conserved role for the Drosophila Pax6 homolog Eyeless in differentiation and function of insulin-producing neurons

Abstract

Insulin/insulin-like growth factor (IGF) signaling constitutes an evolutionarily conserved pathway that controls growth, energy homeostasis, and longevity. In Drosophila melanogaster, key components of this pathway are the insulin-like peptides (Dilps). The major source of Dilps is a cluster of large neurons in the brain, the insulin-producing cells (IPCs). The genetic control of IPC development and function is poorly understood. Here, we demonstrate that the Pax6 homolog Eyeless is required in the IPCs to control their differentiation and function. Loss of eyeless results in phenotypes associated with loss of insulin signaling, including decreased animal size and increased carbohydrate levels in larval hemolymph. We show that mutations in eyeless lead to defective differentiation and morphologically abnormal IPCs. We also demonstrate that Eyeless controls IPC function by the direct transcriptional control of one of the major Dilps, dilp5. We propose that Eyeless has an evolutionarily conserved role in IPCs with remarkable similarities to the role of vertebrate Pax6 in ␤ cells of the pancreas.energy homeostasis ͉ evolutionarily conserved ͉ growth control ͉ target gene ͉ transcription factor

Conserved role for the Dachshund protein with Drosophila Pax6 homolog Eyeless in insulin expression

“…The expression levels of dilp2, dilp3, and dilp5 were measured by realtime quantitative RT-PCR (qRT-PCR) using mRNA that was extracted from adult heads. Consistent with previous work (17), the knockdown of ey significantly suppressed dilp5 expression ( Fig. S1 and SI Results and Discussion).…”

“…In contrast, a strong RNAi line against ey (RNAi #3) caused a severe reduction in dilp5 and dilp2 expression in all larval stages, even in the absence of Dcr-2 ( Fig. 2C), indicating that ey plays a critical role in the differentiation and/or normal function of IPCs (SI Results and Discussion) (17).…”

“…Ey binds directly to the dilp5 promoter and controls dilp5 expression (17). Therefore, we extended our time-course analysis to ey mutants.…”

“…Drosophila Eyeless (Ey) has been reported to control IPC function, and this role is similar to that of the vertebrate homolog Pax6 in the pancreatic β-cells (15)(16)(17). Ey plays dual roles in IPCs; it controls neuronal differentiation and directly controls dilp5 expression (17). However, it is unclear how a single factor regulates two different processes in the IPCs during development.…”

“…Indeed, the differentiation of pancreatic β-cells involves the expression of many genes that also are expressed during neuronal development (13,14). Drosophila Eyeless (Ey) has been reported to control IPC function, and this role is similar to that of the vertebrate homolog Pax6 in the pancreatic β-cells (15)(16)(17). Ey plays dual roles in IPCs; it controls neuronal differentiation and directly controls dilp5 expression (17).…”