From Cell States to Cell Fates: How Cell Proliferation and Neuronal Differentiation Are Coordinated During Embryonic Development

Abstract

The central nervous system (CNS) exhibits an extraordinary diversity of neurons, with the right cell types and proportions at the appropriate sites. Thus, to produce brains with specific size and cell composition, the rates of proliferation and differentiation must be tightly coordinated and balanced during development. Early on, proliferation dominates; later on, the growth rate almost ceases as more cells differentiate and exit the cell cycle. Generation of cell diversity and morphogenesis takes place concomitantly. In the vertebrate brain, this results in dramatic changes in the position of progenitor cells and their neuronal derivatives, whereas in the spinal cord morphogenetic changes are not so important because the structure mainly grows by increasing its volume. Morphogenesis is under control of specific genetic programs that coordinately unfold over time; however, little is known about how they operate and impact in the pools of progenitor cells in the CNS. Thus, the spatiotemporal coordination of these processes is fundamental for generating functional neuronal networks. Some key aims in developmental neurobiology are to determine how cell diversity arises from pluripotent progenitor cells, and how the progenitor potential changes upon time. In this review, we will share our view on how the advance of new technologies provides novel data that challenge some of the current hypothesis. We will cover some of the latest studies on cell lineage tracing and clonal analyses addressing the role of distinct progenitor cell division modes in balancing the rate of proliferation and differentiation during brain morphogenesis. We will discuss different hypothesis proposed to explain how progenitor cell diversity is generated and how they challenged prevailing concepts and raised new questions.

Keywords: cell fate; cell state; morphogenesis; neural stem cells (NSC); neurogenesis; neuronal differentiation.

FIGURE 1

Cell fates vs. cell states and new approaches for cell lineage reconstruction. (A) Overview of the current scenarios for cells progressing toward differentiation. Scenario A shows progenitor cells transitioning toward specification and commitment to finally differentiate. New high-throughput sequencing technologies (RNA-seq, ATAC-seq, and single cell sequencing) produce large volumes of data providing transcriptomic signatures. This unveils the emergence of different cell states within a cell fate depicted as color hues in Scenario B. (B) Future challenges to comprehend how cells acquire their fate. Next generation tools might blend big data provided by (i) 4D imaging that informs us about cell hierarchies and behaviors (see transverse views of zebrafish hindbrain over time; cell nuclei are in magenta and plasma membranes in green), (ii) clonal analyses, which informs about tissue growth; and (iii) transcriptomic signatures telling us about GRN in order to fill the gap between genetic determinism, cell behavior and cell fate while keeping the morphological context. The best scenario would be to blend such amount information in order to understand cell behaviors and to generate full cell lineages.