Assessing the transition state model for cellular differentiation in vivo: a case study of zebrafish neuromesodermal progenitors
type: CreativeWork
description: During the process of cellular differentiation, stem or progenitor cells undergo a sequence of cell state changes before acquiring the characteristics of their destination fate. The transition state model proposes that a transient window of increased gene expression stochasticity and diversity precedes the coherent entry into the differentiated state. As the model has been assessed primarily via in vitro studies, I sought to explore whether a similar phenomenon can be observed within a cell population in vivo. In my thesis, I chose to study the neuromesodermal progenitors (NMps) in the zebrafish tailbud due to their relative biological simplicity. These progenitors co-express sox2 (neural marker) and tbxta (mesodermal marker) and differentiate into the posterior spinal cord or paraxial mesodermal lineages at the late somitogenesis stages, in the absence of other cellular processes such as proliferation, apoptosis and extensive mixing. Thus, I was able to relate cell states to cell fates as I analysed the gene expression heterogeneities in the NMp population in situ. To assess whether the transition state model applies to zebrafish NMp differentiation in vivo, I established four experimental predictions. First, there should be an increase in the heterogeneities of sox2 and tbxta expression in the NMps as they enter the transition state. During mid to late somitogenesis, I found that the heterogeneities in sox2 and tbxta expression as well as the variability in cell number peaked at the 24-somite stage (24ss), which is when NMps contribute to the developing axis. Second, as a transition state results from the flattening of the progenitor attractor during a bifurcation event, it should display several quantitative signatures of a critical transition. By analysing a high-dimensional single-cell RNA-seq dataset at 18ss, I observed an increase in the critical transition index and transcriptional noise in the NMp population relative to its derivatives. Next, to follow the …
abstract: During the process of cellular differentiation, stem or progenitor cells undergo a sequence of cell state changes before acquiring the characteristics of their destination fate. The transition state model proposes that a transient window of increased gene expression stochasticity and diversity precedes the coherent entry into the differentiated state. As the model has been assessed primarily via in vitro studies, I sought to explore whether a similar phenomenon can be observed within a cell population in vivo. In my thesis, I chose to study the neuromesodermal progenitors (NMps) in the zebrafish tailbud due to their relative biological simplicity. These progenitors co-express sox2 (neural marker) and tbxta (mesodermal marker) and differentiate into the posterior spinal cord or paraxial mesodermal lineages at the late somitogenesis stages, in the absence of other cellular processes such as proliferation, apoptosis and extensive mixing. Thus, I was able to relate cell states to cell fates as I analysed the gene expression heterogeneities in the NMp population in situ. To assess whether the transition state model applies to zebrafish NMp differentiation in vivo, I established four experimental predictions. First, there should be an increase in the heterogeneities of sox2 and tbxta expression in the NMps as they enter the transition state. During mid to late somitogenesis, I found that the heterogeneities in sox2 and tbxta expression as well as the variability in cell number peaked at the 24-somite stage (24ss), which is when NMps contribute to the developing axis. Second, as a transition state results from the flattening of the progenitor attractor during a bifurcation event, it should display several quantitative signatures of a critical transition. By analysing a high-dimensional single-cell RNA-seq dataset at 18ss, I observed an increase in the critical transition index and transcriptional noise in the NMp population relative to its derivatives. Next, to follow the …
author: Toh, Kane
language: eng
keywords: NMps, Developmental Biology, Transition State theory, Cell fate decision making, Neuromesodermal progenitors
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2021-08-27
date modified: 2026-07-22T22:24:30Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.78756