Unlike in other organs, changes in cell numbers in the brain cannot be compensated by changes in cell size. This explains why the brain is particularly sensitive to defects in cell division and requires specific proliferation control mechanisms.
Drosophila melanogaster neural stem cells and mammalian cortical progenitors have emerged as the key model systems to study proliferation control in the brain.
In D. melanogaster, the segregating determinants NUMB, Prospero (PROS) and Brain tumour (BRAT) establish differential proliferation control in the two daughter cells of neural progenitors. In mammals, the asymmetric inheritance of apical and basal processes, asymmetry between the two centrosomes and interactions between the daughter cells through Notch signalling act redundantly to establish unequal cell fates.
D. melanogaster neural stem cells pass through distinct temporal stages, starting with their activation by insulin receptor signalling through the expression of a temporal transcription factor cascade to a switch in metabolic activity that ultimately triggers their shrinkage and differentiation.
In mammals, homologues of the D. melanogaster temporal cascade seem to act in conjunction with distinct events, such as the switch from neurogenesis to gliogenesis, which is dependent on the JAK–STAT (Janus kinase–signal transducer and activation of transcription) and Notch pathways.
Metabolic regulation plays a crucial role in proliferation control in both D. melanogaster neural stem cells and in adult mammalian neurogenesis.
Defects in proliferation control can lead to diseases such as microcephaly or megalencephaly.
Neural circuit function can be drastically affected by variations in the number of cells that are produced during development or by a reduction in adult cell number owing to disease. For this reason, unique cell cycle and cell growth control mechanisms operate in the developing and adult brain. In Drosophila melanogaster and in mammalian neural stem and progenitor cells, these mechanisms are intricately coordinated with the developmental age and the nutritional, metabolic and hormonal state of the animal. Defects in neural stem cell proliferation that result in the generation of incorrect cell numbers or defects in neural stem cell differentiation can cause microcephaly or megalencephaly.
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The authors thank all the members of J.A.K.'s laboratory for their helpful discussion. Work in J.A.K.'s laboratory is supported by the Austrian Academy of Sciences, the Austrian Science Fund (Fonds zur Förderung der wissenschaftlichen Forschung (FWF); grants I_552-B19 and Z_153_B09), and an advanced grant of the European Research Council (ERC).
The authors declare no competing financial interests.
The phenomenon by which cells cease to proliferate; usually associated with ageing.
- Transit amplifying cells
A progenitor cell population with the potential to develop into restricted number of cell types and limited proliferative potential.
- Neural progenitor lineages
Neuronal lineages that originate from a neural stem cell.
- Fat body
An organ in Drosophila melanogaster that combines the functions of mammalian fat tissue and liver.
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Homem, C., Repic, M. & Knoblich, J. Proliferation control in neural stem and progenitor cells. Nat Rev Neurosci 16, 647–659 (2015). https://doi.org/10.1038/nrn4021
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