Researchers have identified that the precisely timed transcription of two genes named grim and reaper is responsible for the targeted death of neurons within the developing nervous system of female flies. This group of neurons normally survive in males and play a key role in the neural circuits underlying courtship song.
More cells are born than are needed in the adult
Neurons are highly specialised to perform specific roles, for example neurons that innervate muscles are extremely long so that they can reach from the nervous system to their distant targets in the body, whereas other types of neurons that communicate with cells close by are highly branched and span short distances. To build a functional nervous system you need the right type of components and the right number of those components. One key mechanism that orchestrates this patterning is programmed cell death during development. Cell death patterns the nervous system by deletion, ensuring that the appropriate numbers of specific neuron subtypes are present, so that they can be wired together later in development.
Just as Michelangelo sculpted the statue of David from the gargantuan block of marble known as 'the giant', the segmental and sex-specific circuits in the fly are carved piece by piece from developing neurons using programmed cell death. Despite decades of work on the molecules that execute programmed cell death, little is known about the mechanisms that control when and where it happens.
Dr Darren Williams, Reader in Developmental Neurobiology at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN).
Genes grim and reaper are essential for creating the adult nervous system
In a new study, published in Development, King's College London researchers at IoPPN's Centre for Developmental Neurobiology investigated how the developing neurons are assigned their future roles in the adult fly. The researchers found that the transcription of two pro-death genes, called reaper and grim, decide the fate of the cells by selectively killing those that will not be required in the adult nervous system in a process known as programmed cell death.
"This work is one of the most exciting things to come out of our lab. The conceptual framework it forwards and its implications are startling. The work gives us an in-road into the logic of how lineages of neurons can be finely tuned during development and in evolution," commented Dr Darren Williams, the senior author on the study. "Until now this specific type of cell death has been largely ignored, even though it removes more than half of the neurons that are born in flies."
Time-specific genetic switch controls selective death of 'song neurons' in females
Using fluorescent labels and new genetic tools, the team tested whether differences in the nervous system between sexes were caused by precisely timed gene expression events. At certain windows during development, a subset of neurons in female flies die. These neurons are required in adult males to produce the 'love song' that females listen to during courtship. When the researchers removed reaper and grim from developing flies, this subset of neurons remained in the females, showing that this process of cell death is instrumental in determining the neural differences between sexes. The team also artificially switched on a gene that causes flies to develop into females, in a small number of neurons in male flies. They found that this 'turned up' the levels of grim and reaper expression and killed the same type of neurons that naturally die in the developing females.
This same 'switching on' of a death program just after a neuron has been born also sculpts regional differences throughout the length of the nervous system. Understanding how such patterns of death are orchestrated during development is critical for understanding how nervous systems are built.
When we saw that differences between males and female nervous systems were regulated by this specific mode of death in neurons that were the recently born we realised just how critical type of death is for sculpting developing neural circuitry
Dr Connor Sproston, first author on the study
The research was performed in collaboration with researchers at the Tokyo University of Science and Technology. "Being able to collaborate with the Kondo Lab really elevated the work through the generation of powerful new genetic tools. Visiting Dr Kondo in the summer of 2019 was a definite highlight of my time working on the project," said Dr Connor Sproston, the first author of the study.
Hemilineage-specific deployment of the pro-apoptotic RHG genes reaper and grim during neurogenesis sculpts segment and sex-specific neural network composition in Drosophila (DOI:10.1242/dev.204902) was published in Development.
This research was funded with support from the Biotechnology and Biological Sciences Research Council
