A Shh/Gli-driven three-node timer motif controls temporal identity and fate of neural stem cells

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.

Temporal patterning of the central nervous system by a shared transcription factor code

“…The data show that the temporal pattern of both neurons and progenitors continues to advance in the absence of TGFβ pathway activity. This is consistent with observations from the ventral hindbrain, where ablation of Tgfbr1 delays but does not abrogate the switch from MNs to serotonergic neurons and in Gdf11 mutants in the spinal cord, where the onset of oligodendrocyte formation is delayed but not prevented (Dias et al, 2014, 2020; Shi and Liu, 2011). Together this suggests that other extrinsic signals, or cell-intrinsic timers, must exist that promote temporal progression.…”

Precision of morphogen gradients in neural tube development

“…Even for a relatively pessimistic value of 0.6 for production, degradation and diffusion, we find that the gradient imprecision is 1–3 cells over several hundreds of micrometers, providing sufficiently accurate positional information to pattern a large domain. Local fluctuations can be reduced further through spatial and temporal averaging 5 , 41 , 42 . Moreover, in zebrafish, NT progenitor boundaries are sharpened by cell sorting 43 , 44 .…”

Inference of Morphogen Gradient Precision from Molecular Noise Data

“…Even for a relatively pessimistic value of 0.6 for production, degradation and diffusion, we find that the gradient imprecision is 1-3 cells over several hundreds of micrometers, providing sufficiently accurate positional information to pattern a large domain. Local fluctuations can be reduced further through spatial and temporal averaging [30][31][32]. Moreover, in zebrafish, NT progenitor boundaries are sharpened by cell sorting [33,34].…”