Systemic and local signalling regulating neural stem cell proliferation

Neural stem cells (NSCs) in the brain can be reactivated to exit quiescence and generate new cells in response to injury or disease. Determining the specific signals involved in NSC reactivation is essential to understanding neural regeneration. Investigating NSCs in *Drosophila melanogaster* provides a powerful model due to ease of identification of quiescent NSCs and a plethora of genetic and molecular tools available to study the nervous system *in vivo*. During development, *Drosophila* NSCs reactivate in response to dietary amino acids sensed by the fat body, a sensor organ analogous to liver and adipose tissue in mammals. Previously unknown signals from the fat body are transmitted to the bloodbrain barrier (BBB) glia on the surface of the brain. The glia secrete insulin-like peptides, which are received by the insulin receptor on NSCs, inducing their reactivation. To identify the fat body-derived signals sent to the brain, I used Targeted DamID to generate transcriptional profiles of the fat body under fed and starved conditions. I discovered upregulation of *dpp (decapentaplegic)*, a transforming growth factor (TGFβ) secreted morphogen, after feeding. Knockdown of Dpp in the fat body severely impaired NSC reactivation. Similarly, knocking down a key receptor for Dpp, Tkv (Thickveins), in the BBB glia led to severely impaired NSC reactivation. To compare gene expression in glial subtypes under fed and starved conditions, I generated single-cell RNA sequencing datasets. I found Dpp to be upregulated in BBB glia in response to feeding and functional experiments showed that Dpp signalling in the glial niche is required for NSC reactivation. The presence of Medea transcription factor binding sites at the dIlp6 locus and impaired NSC reactivation when Medea is knocked down in the BBB glia suggest that Dpp signalling may regulate expression of dIlp6. Knockdown of Tkv in the NSCs themselves did not affect reactivation, suggesting autocrine Dpp signalling in the BBB glia in response to interorgan Dpp signalling from the fat body to the brain. The findings may help understand how to induce neural stem cell proliferation after brain damage or neurodegeneration.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Arman, Diana

Advisor dc:contributor.advisor

• Brand, Andrea

• bioinformatics
• glia
• inter-organ signalling
• neural development
• neural stem cell
• scRNA-seq
• single-cell transcriptomics
• stem cell
• stem cell niche

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/96780c47-e1a4-4bd6-98aa-a2529791f649/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.97240

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/351011