Abstract
How time is measured by neural stem cells during temporal neurogenesis has remained unresolved. By combining experiments and computational modeling, we 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 down-regulation of Gli transcription. The circuitry conforms an incoherent feed-forward loop, whereby Gli proteins not only promote expression of Phox2b and thereby MN-fate but also account for a delayed activation of a self-promoting transforming growth factor-β (Tgfβ) node triggering a fate switch by repressing Phox2b. Hysteresis and spatial averaging by diffusion of Tgfβ counteract noise and increase temporal accuracy at the population level, providing a functional rationale for the intrinsically programmed activation of extrinsic switch signals in temporal patterning. Our study defines how time is reliably encoded during the sequential specification of neurons.
Highlights
Time is a central axis of information during embryogenesis, but few mechanisms explaining the timing of developmental events have been resolved [1,2,3,4]
Sonic hedgehog (Shh)/Gli signaling promotes expression of Phox2b The sequential specification of motor neurons (MNs), 5HTNs, and oligodendrocyte precursors (OPCs) by Nkx2.2+ neural stem cells (NSCs) is recapitulated in mouse embryonic stem cell (ESC) cultures in response to timed activation of Shh and retinoic acid signaling [15]
To define genome-wide transcriptional changes over time, we determined the transcriptome of Nkx2.2+ NSCs isolated at different time points by RNA sequencing (RNA-seq)
Summary
Time is a central axis of information during embryogenesis, but few mechanisms explaining the timing of developmental events have been resolved [1,2,3,4]. In the forming central nervous system (CNS), defined pools of multipotent neural stem cells (NSCs) produce distinct cell types in a specific sequential order and over defined time frames. In this process, aging NSCs become progressively restricted in their developmental potential by losing competence to generate early- born cell types [5], and genome-wide analyses have revealed that NSCs undergo dynamic transcriptional changes over time [6]. The composition and functional properties of time-encoding circuitries determining time frames and point of transitions have not been resolved in any model system [7, 8]. Biological timers regulating temporal neurogenesis are likely to exhibit properties that counterbalance noise in regulatory networks, but how this is achieved at the molecular level remains unknown
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