Research
Discovering how stem cells are maintained in a multipotent state and how their progeny differentiate into distinct cellular fates is a key step in the therapeutic use of stem cells to repair tissues after damage or disease. We are investigating the genetic networks that regulate neural stem cell behaviour. Neural stem cells in the adult brain exist primarily in a quiescent state but can be reactivated in response to changing physiological conditions. How do stem cells sense and respond to metabolic changes? In the Drosophila central nervous system, quiescent neural stem cells are reactivated synchronously in response to a nutritional stimulus. We showed that feeding triggers insulin production by blood-brain barrier glial cells, activating the insulin/IGF pathway in underlying neural stem cells and stimulating their growth and proliferation. More recently, we discovered that gap junctions in the blood-brain barrier glia mediate the influence of metabolic changes on stem cell behaviour, enabling glia to respond to nutritional signals and reactivate quiescent stem cells.
The ability to reprogram differentiated cells into a pluripotent state has revealed that the differentiated state is plastic and reversible. Mechanisms must be in place to prevent neurons from dedifferentiating to a multipotent, stem cell-like state. We discovered that the BTB-Zn finger transcription factor, Lola, is required to maintain neurons in a differentiated state. In lola mutants, neurons dedifferentiate, turn on neural stem cell genes and begin to divide, forming tumours. Thus, neurons rather than stem cells or intermediate progenitors are the tumour-initiating cells in lola mutants.
Cell-type specific transcriptional profiling is key to understanding cell fate specification and function. We developed ‘Targeted DamID’ (TaDa) to enable cell-specific profiling without cell isolation. TaDa permits genome-wide profiling of DNA- or chromatin-binding proteins without cell sorting, fixation or affinity purification.
Co-workers
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Alex Donovan |
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Anna Malkowska |
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Bernardo Delarue Bizzini |
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Cian Doherty |
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Nemira Zilinskaite |
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Oriol Llora Batlle |
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Tara Srinivas |
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Thomas Genais |
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Amy Foreman |
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Maire Brace |
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Catherine Davidson |
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Christine Turner |
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Diana Arman |
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Jocelyn Tang |
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Leia Judge |
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Rebecca Yakob |
Publications
Hakes AE & Brand AH (2020) Tailless/TLX reverts intermediate neural progenitors to stem cells driving tumourigenesis via repression of asense/ ASCL1. eLife 9:e53377.
Otsuki L & Brand AH (2019) Dorsal-ventral differences in neural stem cell quiescence are induced by p57KIP2/Dacapo. Developmental Cell. 49:293-300.
Hakes AE, Otsuki L, Brand AH (2018) A newly discovered neural stem cell population is generated by the optic lobe neuroepithelium during embryogenesis in Drosophila melanogaster. Development Sep 25;145(18). doi: 10.1242/dev.166207.
Otsuki L & Brand AH (2018) Cell cycle heterogeneity directs the timing of neural stem cell activation from quiescence. Science. 360(6384):99-102.
Spéder P & Brand AH (2018) Systemic and local cues drive neural stem cell niche remodelling during neurogenesis in Drosophila. eLife. Jan 4;7. doi: 10.7554/eLife.30413.
Cheetham SW & Brand AH (2018) RNA-DamID reveals cell-type-specific binding of roX RNAs at chromatin-entry sites. Nat Struct Mol Biol Jan;25(1):109-114.
