A Spacetime Odyssey of Neural Progenitors to Generate Neuronal Diversity

Abstract

To understand how the nervous system develops from a small pool of progenitors during early embryonic development, it is fundamentally important to identify the diversity of neuronal subtypes, decode the origin of neuronal diversity, and uncover the principles governing neuronal specification across different regions. Recent single-cell analyses have systematically identified neuronal diversity at unprecedented scale and speed, leaving the deconstruction of spatiotemporal mechanisms for generating neuronal diversity an imperative and paramount challenge. In this review, we highlight three distinct strategies deployed by neural progenitors to produce diverse neuronal subtypes, including predetermined, stochastic, and cascade diversifying models, and elaborate how these strategies are implemented in distinct regions such as the neocortex, spinal cord, retina, and hypothalamus. Importantly, the identity of neural progenitors is defined by their spatial position and temporal patterning factors, and each type of progenitor cell gives rise to distinguishable cohorts of neuronal subtypes. Microenvironmental cues, spontaneous activity, and connectional pattern further reshape and diversify the fate of unspecialized neurons in particular regions. The illumination of how neuronal diversity is generated will pave the way for producing specific brain organoids to model human disease and desired neuronal subtypes for cell therapy, as well as understanding the organization of functional neural circuits and the evolution of the nervous system.

A quantitative characterization of early neuron generation in the developing zebrafish telencephalon

“…This shows that soon after the onset of telencephalic neurogenesis, distinct neuronal cell fates are specified that emerge in spatially distinct domains. This positional neuronal diversity probably depends on dorsoventral morphogen gradients similar to that in the spinal cord (Ge et al, 2022;Sagner and Briscoe, 2019).…”

“…During embryonic development of the vertebrate brain, spatially distinct regions with specific cognitive and information-processing functions emerge. Underlying these different functions is the spatiotemporally controlled generation of the different types of neurons present in each brain region (Ge et al, 2022;Lodato and Arlotta, 2015;Shohayeb et al, 2021). At the root of this neuronal diversity are neural stem and progenitor cells (NPCs) that are present within the developing neuroepithelium and undergo cell division to generate new neurons (Ortiz-Álvarez and Spassky, 2021).…”

“…Despite the advances made in understanding how the production of neuronal diversity from embryonic NPCs is regulated (Ge et al, 2022;Lodato and Arlotta, 2015), our understanding of the molecular and cell biological mechanisms underlying individual NPC division mode and fate decisions is limited. For instance, studies using various NPC lineage-tracing methods have demonstrated that there is remarkable heterogeneity in the division modes used by individual NPCs in the vertebrate nervous system (Dong et al, 2012;Gao et al, 2014;Gomes et al, 2011;He et al, 2012;Hevia et al, 2021;Llorca et al, 2019).…”

“…For instance, studies using various NPC lineage-tracing methods have demonstrated that there is remarkable heterogeneity in the division modes used by individual NPCs in the vertebrate nervous system (Dong et al, 2012;Gao et al, 2014;Gomes et al, 2011;He et al, 2012;Hevia et al, 2021;Llorca et al, 2019). Also, it is not clear whether the embryonic NPCs present at the onset of neurogenesis are equipotent in their ability to produce the different types of neurons (Ge et al, 2022;Zechner et al, 2020). In order to understand the factors and processes underlying individual NPC biology in each part of the nervous system, it is important to have a clear picture of the timing of neurogenesis and NPC division mode changes in each brain region.…”

A quantitative characterization of early neuron generation in the developing zebrafish telencephalon

“…During embryonic development of the vertebrate brain, spatially distinct regions with specific cognitive and informationprocessing functions emerge. Underlying these different functions is the spatiotemporally controlled generation of the different types of neurons present in each brain region (Ge et al, 2022;Lodato & Arlotta, 2015;Shohayeb et al, 2021).…”