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

Abstract

The molecular mechanisms that ensure the reproducible generation of neuronal diversity in the vertebrate nervous system are incompletely understood. Here we provide evidence of a temporal patterning program consisting of cohorts of transcription factors expressed in neurons generated at successive developmental timepoints. This program acts in parallel to spatial patterning, diversifying neurons throughout the nervous system and in neurons differentiated in-vitro from stem cells. We demonstrate the TGFβ signalling pathway controls the pace of the temporal program. Furthermore, targeted perturbation of components of the temporal program, Nfia and Nfib, reveals their requirement for the generation of late-born neuronal subtypes. Together, our results provide evidence for the existence of a previously unappreciated global temporal program of neuronal subtype identity and suggest that the integration of spatial and temporal patterning programs diversifies and organises neuronal subtypes in the vertebrate nervous system.

General and cell-type-specific aspects of the motor neuron maturation transcriptional program

“…In the olfactory epithelium, they are involved in the correct specification of late born olfactory receptors (Bashkirova et al, 2020). They are required for the correct specification of late born neuron types in various other regions including the dorsal spinal cord (Sagner et al, 2020). And, they have been shown to accelerate glial competency in human included pluripotent stem cells (Tchieu et al, 2019).…”

The regulatory landscape of cells in the developing mouse cerebellum

“…Indeed, many CREs show temporally dynamic activity patterns that are shared between germinal zones (Fig. 4D), arguing for a mode of cell fate induction through shared temporal cues ( 4 , 9 , 57 ).…”

“…Although we found that the dynamics of CRE activity and conservation across development can mostly be explained by cellular differentiation and maturation, additional temporal differences could be present, even between cells at the same differentiation state. Such differences could arise from intrinsic temporal patterning cues, as recently described in the context of cell fate specification ( 57 , 68 ), as well as extrinsic factors, such as changes in the availability of a morphogen or a ligand, synaptic simulation and interactions with neighboring cells ( 16 ). To assess the contribution of such temporal signals we focused on GCs, because these cells have a protracted differentiation trajectory (E13-P14) and do not have distinct temporally-specified subtypes.…”

“…These could involve intrinsic patterning through a shared temporal code, as recently suggested for multiple regions of the central nervous system (57). In support of this hypothesis, we found that late progenitor populations (E13-P7) are enriched for motifs of the NFI TF family, which is associated with the generation of late-born neurons in several brain regions (57). Additionally, common extrinsic cues, such as factors secreted from the choroid plexus might also explain the coordinated changes in CRE activity across germinal zones (4).…”

Single-cell transcriptomics of the early developing mouse cerebral cortex disentangles the spatial and temporal components of neuronal fate acquisition

“…Sharp segregation of progenitor domains in the developing spinal cord has long suggested that spatial patterning is a key driver of neuronal diversity in the central nervous system (CNS). However, temporal patterning was recently proposed to be also at play and to involve the same gene networks throughout the CNS (Sagner et al, 2020). In the neocortex, the graded expression of patterning genes, the sequential production of deep and upper layers neurons and the changes in the transcriptomic signature associated with AP maturation (Okamoto et al, 2016; Telley et al, 2019) clearly point to the importance of temporal mechanisms.…”