A shared transcriptional code orchestrates temporal patterning of the central nervous system

Abstract

The molecular mechanisms that produce the full array of neuronal subtypes in the vertebrate nervous system are incompletely understood. Here, we provide evidence of a global temporal patterning program comprising sets of transcription factors that stratifies neurons based on the developmental time at which they are generated. This transcriptional code acts throughout the central nervous system, in parallel to spatial patterning, thereby increasing the diversity of neurons generated along the neuraxis. We further demonstrate that this temporal program operates in stem cell−derived neurons and is under the control of the TGFβ signaling pathway. Targeted perturbation of components of the temporal program, Nfia and Nfib, reveals their functional requirement for the generation of late-born neuronal subtypes. Together, our results provide evidence for the existence of a previously unappreciated global temporal transcriptional program of neuronal subtype identity and suggest that the integration of spatial and temporal patterning mechanisms diversifies and organizes neuronal subtypes in the vertebrate nervous system.

Integration of Spatial and Temporal Patterning in the Invertebrate and Vertebrate Nervous System

“…(B) Mammalian temporal patterning and neurons generated in each temporal window. Upper panel: Birth date of cortical projection neurons ( Caviness, 1982 ) and V1 spinal interneuron ( Stam et al, 2012 ) with temporal transcription factor expression in neural progenitors at each temporal window ( Sagner et al, 2021 ); lower panel: Birth date of retinal cells and corresponding temporal transcription factors in retinal progenitors [RGC: retinal ganglion cell; HC: horizontal cell; AC: amacrine cell; Rod: rod cell (photoreceptor); BC: bipolar cell; MC: Müller cell] ( Elliott et al, 2008 ; Mattar et al, 2015 ; Javed et al, 2020 ). (C) Different regions in the fly nervous system undergo different cascades of temporal factors to generate different types of neurons.…”

“…In mammals, recent studies have systematically discovered a set of birthdate markers that are shared between different cell types in the hindbrain and spinal cord of human and mouse ( Delile et al, 2019 ; Osseward et al, 2021 ; Rayon et al, 2021 ; Figure 2B ), and the expression of these markers are consistent with known subtypes within several cardinal classes of spinal neurons ( Roy et al, 2012 ; Bikoff et al, 2016 ; Hayashi et al, 2018 ). Some of these birthdate markers are required for early-vs. late-born neuronal fate in neurons (e.g., in the mammalian cortex, Satb2 is required for later-born callosal neurons from layer 2 to 5, and Fezf2 and Ctip2 are necessary for early-born ones in layer 5) ( Chen et al, 2005 , 2008 ; Alcamo et al, 2008 ; Britanova et al, 2008 ) and in progenitors (e.g., Nfia and Nfib for the generation of late-born neurons in the retina and ventral spinal interneurons) ( Xie et al, 2020 ; Sagner et al, 2021 ). Consistent with the idea that neural progenitor temporal factors specify the fate of daughter neurons, cortical neurons inherit the gene modules that are present in radial glia at the stage when the neurons were generated ( Telley et al, 2019 ), and the late-born fate regulators Nfia/b/x directly regulate late-born fate associated genes in the mammalian retina ( Clark et al, 2019 ; Xie et al, 2020 ; Lyu et al, 2021 ).…”

“…The recent advent of high-throughput profiling techniques not only made possible the discovery of a shared set of temporal regulators across different vertebrate neuronal tissues ( Lu et al, 2020 ; Sagner et al, 2021 ) but also opened the opportunity to understand the gene regulatory networks governed by these temporal factors ( Telley et al, 2019 ; Lyu et al, 2021 ) and other birthdate-specific post-mitotic regulators ( Di Bella et al, 2021 ). Our rapidly expanding knowledge of the molecular logic of spatiotemporal integration and fate specification in various species will set the stage for more comparative studies, such as the investigation of how the targets of conserved spatiotemporal regulators differ between species, how novel spatial domains or temporal windows emerge, and, ultimately, how new cell types are generated during development and evolution.…”

mRNA Translation Is Dynamically Regulated to Instruct Stem Cell Fate

“…How gene expression programs controlling quiescence, proliferation, self-renewal, and differentiation can be both stable and plastic is the subject of much study, often focusing on understanding the transcriptional networks that maintain cell identity and the inputs that destabilize these networks and allow cells to change fate. Our understanding of these networks has grown and is continually being refined, showing that various stable network states exist and explaining transitions between these states ( Kim et al, 2008 ; Moignard et al, 2013 ; Theunissen and Jaenisch, 2017 ; Kim et al, 2020 ; Sagner et al, 2021 ). Furthermore, we have gained considerable understanding of the epigenetic changes that reinforce these transcriptional changes and ensure that stem cells maintain plasticity in gene expression while differentiating cells gradually become restricted in potential ( Lunyak and Rosenfeld, 2008 ; Ohbo and Tomizawa, 2015 ; Theunissen and Jaenisch, 2017 ; Ding et al, 2021 ).…”

Regulation of developmental hierarchy inDrosophilaneural stem cell tumors by COMPASS and Polycomb complexes

“…1A) (26,36). Descriptions of similar temporal patterning systems are emerging in mammalian neural stem cells, but they remain much less characterized (4,(37)(38)(39).…”