Postmitotic Specification of Drosophila Insulinergic Neurons from Pioneer Neurons

Abstract

Insulin and related peptides play important and conserved functions in growth and metabolism. Although Drosophila has proved useful for the genetic analysis of insulin functions, little is known about the transcription factors and cell lineages involved in insulin production. Within the embryonic central nervous system, the MP2 neuroblast divides once to generate a dMP2 neuron that initially functions as a pioneer, guiding the axons of other later-born embryonic neurons. Later during development, dMP2 neurons in anterior segments undergo apoptosis but their posterior counterparts persist. We show here that surviving posterior dMP2 neurons no longer function in axonal scaffolding but differentiate into neuroendocrine cells that express insulin-like peptide 7 (Ilp7) and innervate the hindgut. We find that the postmitotic transition from pioneer to insulin-producing neuron is a multistep process requiring retrograde bone morphogenetic protein (BMP) signalling and four transcription factors: Abdominal-B, Hb9, Fork Head, and Dimmed. These five inputs contribute in a partially overlapping manner to combinatorial codes for dMP2 apoptosis, survival, and insulinergic differentiation. Ectopic reconstitution of this code is sufficient to activate Ilp7 expression in other postmitotic neurons. These studies reveal striking similarities between the transcription factors regulating insulin expression in insect neurons and mammalian pancreatic β-cells.

Author Summary

Genetic studies using invertebrate model organisms such as Drosophila have provided many new insights into the functions of insulin and related peptides. It has, however, been more difficult to use Drosophila to study the regulation of insulin, at least in part because the relevant insulinergic cell lineages were not well characterised. Here, we have identified a cell lineage that generates a single Drosophila insulin-producing neuron. This neuron first functions as a pioneer, guiding the axons of other neurons within the central nervous system of the embryo. It then develops long axons that exit the central nervous system to innervate the gut and also begins to express an insulin-like peptide. Genetic analysis identifies four transcription factors and one extrinsic signal that instruct the pioneer neuron to become an insulin-producing neuron. The analysis also reveals similarities between the genetic programmes specifying insulin production by Drosophila neurons and mammalian pancreatic ß-cells. This suggests that Drosophila may, in the future, prove a useful model system for identifying new regulators of human insulin production.

Abstract

A genetic analysis in the fruit fly reveals similarities between the transcriptional programmes regulating insulin production in mammalian pancreatic β-cells and insect neurons.