Deciphering neural heterogeneity through cell lineage tracing
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Cellular and Molecular Life Sciences
REVIEW
Deciphering neural heterogeneity through cell lineage tracing María Figueres‑Oñate1,2 · Rebeca Sánchez‑González1 · Laura López‑Mascaraque1 Received: 30 July 2020 / Revised: 10 October 2020 / Accepted: 20 October 2020 © The Author(s) 2020
Abstract Understanding how an adult brain reaches an appropriate size and cell composition from a pool of progenitors that proliferates and differentiates is a key question in Developmental Neurobiology. Not only the control of final size but also, the proper arrangement of cells of different embryonic origins is fundamental in this process. Each neural progenitor has to produce a precise number of sibling cells that establish clones, and all these clones will come together to form the functional adult nervous system. Lineage cell tracing is a complex and challenging process that aims to reconstruct the offspring that arise from a single progenitor cell. This tracing can be achieved through strategies based on genetically modified organisms, using either genetic tracers, transfected viral vectors or DNA constructs, and even single-cell sequencing. Combining different reporter proteins and the use of transgenic mice revolutionized clonal analysis more than a decade ago and now, the availability of novel genome editing tools and single-cell sequencing techniques has vastly improved the capacity of lineage tracing to decipher progenitor potential. This review brings together the strategies used to study cell lineages in the brain and the role they have played in our understanding of the functional clonal relationships among neural cells. In addition, future perspectives regarding the study of cell heterogeneity and the ontogeny of different cell lineages will also be addressed. Keywords Clonal analysis · Neural stem cell · Progenitor potential · Cell progeny · Ontogeny · Cell heterogeneity
Introduction
Neural stem cells potential and heterogeneity
One fundamental issue in Neuroscience is how the different lineages in the brain are established and what contributions sibling cells make to the nervous system and how they influence its behavior. The current belief is that there is large cell heterogeneity in the adult brain, raising the question as to how these different cell types are generated during development. However, a fundamental question is whether this heterogeneity is ontogenically determined and if so, what are the physiological implications of this? Thus, lineage tracing has developed from the need to pursue all the progeny of specific neural progenitor cells (NPCs) to determine how complete neural networks are built and the contribution of specific progenitors to these networks.
Neural stem cells (NSCs) are cells that self-renew and that can produce all the lineages present in the adult brain [1]. Thus, the cell diversity in the brain emerges as the progeny of NSCs progress into lineage-restricted NPCs, more committed cell populations with a more limited differentiation and proliferation potential [2]. The transition to a
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