Understanding the core gene regulatory network underlying epidermal stem cell patterning in Caenorhabditis elegans
File(s)
Author(s)
Brozek, Alicja
Type
Thesis or dissertation
Abstract
Despite the breadth of knowledge on C. elegans and its various cells noone has yet described
a Gene Regulatory Network (GRN) underlying the patterning of C. elegans’s hypodermal
stem cells, the seam cells. In this thesis we aim to produce a seam cell GRN with several
different approaches. We start by focusing on three core transcription factors: elt-1, egl-18,
and ceh-16. We construct an initial network at the late L1 stage, a time point where no
cell is actively dividing. To do this we combine mathematical and biological approaches
to construct a minimal GRN. We test our hypotheses informed by this model on a double
mutant of two of the two core genes ceh-16(bp323);egl-18(ga97) and in the process discover
a highly robust, but erroneous seam cell phenotype at the end of larval development. We
further evaluate the network over different time points and delve into the minutiae of the
differences in expression patterns between the 16 seam cells at various time points. We test
their sensitivities and uncover differences between the seam cells. We identify key positional
patterns in the sensitivities of the seam cells to changes in their core network and link these
sensitivities to Wnt signalling. Finally, we dissect the ceh-16(bp323);egl-18(ga97) double
mutant to further elucidate the mechanisms behind its highly robust loss of self-renewal
divisions. Overall in this thesis we incorporate mathematical approaches into the standard
genetics based approaches for GRN inference. We also demonstrate the importance of
maintaining a spatial and temporal resolution when studying the epidermal stem cells of C.
elegans.
a Gene Regulatory Network (GRN) underlying the patterning of C. elegans’s hypodermal
stem cells, the seam cells. In this thesis we aim to produce a seam cell GRN with several
different approaches. We start by focusing on three core transcription factors: elt-1, egl-18,
and ceh-16. We construct an initial network at the late L1 stage, a time point where no
cell is actively dividing. To do this we combine mathematical and biological approaches
to construct a minimal GRN. We test our hypotheses informed by this model on a double
mutant of two of the two core genes ceh-16(bp323);egl-18(ga97) and in the process discover
a highly robust, but erroneous seam cell phenotype at the end of larval development. We
further evaluate the network over different time points and delve into the minutiae of the
differences in expression patterns between the 16 seam cells at various time points. We test
their sensitivities and uncover differences between the seam cells. We identify key positional
patterns in the sensitivities of the seam cells to changes in their core network and link these
sensitivities to Wnt signalling. Finally, we dissect the ceh-16(bp323);egl-18(ga97) double
mutant to further elucidate the mechanisms behind its highly robust loss of self-renewal
divisions. Overall in this thesis we incorporate mathematical approaches into the standard
genetics based approaches for GRN inference. We also demonstrate the importance of
maintaining a spatial and temporal resolution when studying the epidermal stem cells of C.
elegans.
Version
Open Access
Date Issued
2024-04
Date Awarded
2024-10
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Barkoulas, Michalis
Shahrezaei, Vahid
Sponsor
Biotechnology and Biological Sciences Research Council (Great Britain)
Publisher Department
Life Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)