MRC National Institute for Medical Research, London
Science for Health
Lunatic fringe and lateral inhibition
13 July 2009
The development of the nervous system requires that a pool of progenitor cells (the endogenous neural stem cells) is maintained, from which diverse cell types are generated during a period of weeks to months. The maintenance of progenitors depends upon a process called ‘lateral inhibition’. Proneural transcription factors that drive early steps of neuronal differentiation switch on ligands that activate Notch receptor on adjacent cells, which in turn inhibits neurogenesis. Consequently, each forming neuron inhibits the differentiation of its neighbours, and maintains progenitors that are available for neurogenesis at a later time once the neuron has migrated away. Studies of other roles of Notch found that the amount of receptor activation depends upon Fringe proteins, which by attaching sugar molecules to Notch increase or decrease its binding to ligand. Members of the Fringe gene family have long been known to be expressed during neurogenesis, but their role was unclear.
In studies in the lab of David Wilkinson (pictured), in NIMR's Division of Developmental Neurobiology, Nikolas Nikolaou and collaborators found that a Fringe family member, Lunatic Fringe, is required to achieve a sufficient level of lateral inhibition of neurogenesis. Intriguingly, Lunatic Fringe is required in neural progenitors to inhibit their differentiation, yet is switched on downstream of proneural factors that promote neurogenesis. These findings suggest that Lunatic Fringe acts in a feedback loop that limits the upregulation of proneural factors in progenitors by maintaining their sensitivity to lateral inhibition.
The potential therapeutic use of neural stem cells requires understanding of the normal mechanisms that maintain progenitors and regulate differentiation. This research contributes by identifying a role of Lunatic Fringe in the underlying network of cell signalling and transcription factors.
David Wilkinson
Original article
The research findings are published in full in:
Nikolas Nikolaou, Tomomi Watanabe-Asaka, Sebastian Gerety, Martin Distel, Reinhard W. Köster, and David G. Wilkinson (2009)
Lunatic fringe promotes the lateral inhibition of neurogenesis
Development, epub ahead of print. Publisher abstract
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