eprintid: 32513
rev_number: 14
eprint_status: archive
userid: 7110
dir: disk0/00/03/25/13
datestamp: 2022-12-16 07:44:58
lastmod: 2023-08-01 08:36:00
status_changed: 2022-12-16 07:44:58
type: doctoralThesis
metadata_visibility: show
creators_name: Gallo, Elisa
title: FGF signaling and cell state transitions during organogenesis
divisions: 140001
adv_faculty: af-14
abstract: Organogenesis is a complex choreography of morphogenetic processes, patterns and dynamic shape changes as well as the specification of cell fates. Although several molecular actors and context-specific mechanisms have already been identified, our general understanding of the fundamental principles that govern the formation of organs is far from comprehensive.
The application of the concept of ‘rebuild it to understand it’ from synthetic biology represents a promising alternative to the classical approach of ‘break it to understand it’ in order to distill biological understanding from complex developmental processes. According to this ‘rebuilding’ concept, in this study we sought to develop an experimental approach to induce the formation of organs from progenitor cells ‘on demand’ and to investigate the minimum requirements for such a process.
The zebrafish lateral line chain cells are a powerful in vivo model for our study because they are a group of naïve multipotent progenitor cells that display mesenchyme-like features. In order to bring these cells to form organs, we used the well-known role of the FGF signaling pathway as a driver of organogenesis in the lateral line and developed an inducible and constitutively active form of the fibroblast growth factor receptor 1a (chemoFGFR). The cell-autonomous induction of this chemoFGFR in chain cells effectively triggered the formation of fully mature organs and thus enabled spatial and temporal control of the organogenesis process. 
Next, we asked what it takes to form an organ de novo. We used a combination of real-time microscopy, single cell tracking, polarity quantification, and mosaic analysis to study the cell behaviors that result from chemoFGFR induction. The picture that emerges from these analyses is that de novo organs form through a genetically encoded self-assembly process that is based on the pattern of chemoFGFR induction. In this scenario, cells expressing chemoFGFR aggregate into clusters and epithelialize as they sort out of non-expressing cells. We found that this sorting process occurs through cell rearrangement and slithering, which involves an extensive remodeling of the cell-cell contacts.
Chain cells that do not express chemoFGFR can envelop these chemoFGFR expressing cell clusters and form a rim at the cluster periphery. This multi-stage process leads to the establishment of the inside-outside pattern of de novo organs, which is used as a blueprint for cell differentiation. In summary, in this study we provide insights into the mechanisms involved in the self-assembly of organs from a naïve population of progenitor cells.
date: 2023
id_scheme: DOI
id_number: 10.11588/heidok.00032513
ppn_swb: 1854015109
own_urn: urn:nbn:de:bsz:16-heidok-325136
date_accepted: 2021-02-05
advisor: HASH(0x564efd05bdd8)
language: eng
bibsort: GALLOELISAFGFSIGNALI2022
full_text_status: public
place_of_pub: Heidelberg
citation:   Gallo, Elisa  (2023) FGF signaling and cell state transitions during organogenesis.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/32513/1/PhD_Thesis_Elisa_Gallo.pdf