RT Journal Article
SR Electronic
T1 A Shh/Gli-driven three-node timer motif controls temporal identity and fate of neural stem cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 809418
DO 10.1101/809418
A1 José M. Dias
A1 Zhanna Alekseenko
A1 Ashwini Jeggari
A1 Marcelo Boareto
A1 Jannik Vollmer
A1 Mariya Kozhevnikova
A1 Hui Wang
A1 Michael P. Matise
A1 Andrey Alexeyenko
A1 Dagmar Iber
A1 Johan Ericson
YR 2019
UL http://biorxiv.org/content/early/2019/10/17/809418.abstract
AB How time is measured by neural stem cells during temporal neurogenesis has remained unresolved. By combining experiments and computational modelling, we here define a Shh/Gli-driven three-node timer underlying the sequential generation of motor neurons (MNs) and serotonergic neurons in the brainstem. The timer is founded on temporal decline of Gli-activator and Gli-repressor activities established through downregulation of Gli transcription. The circuitry conforms an incoherent feedforward loop, whereby Gli proteins promote expression of Phox2b and thereby MN-fate, but also account for a delayed activation of a self-promoting Tgfβ-node triggering a fate switch by repressing Phox2b. Hysteresis and spatial averaging by diffusion of Tgfβ counteracts noise and increases temporal accuracy at the population level. Our study defines how time is reliably encoded during the sequential specification of neurons.