How to integrate a fate: explicating the context-dependent molecular mechanisms of WNT signalling in early human embryogenesis

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The WNT signalling pathway plays a range of crucial role in embryonic development, stem cell dynamics and cancer (Clevers, 2006, Nature). Whilst developmental and cancer biology are two sides of the same coin, the WNT signalling pathway currently is a field of intense research. However, whilst some of the mechanisms have been characterised, our understanding in a developmental context in our own species requires a sophisticated interrogation. A cross-species transcriptomic analysis revealed a previously unappreciated role for WNT signalling in human and monkey preimplantation embryonic development (Boroviak et al., 2015; Stirparo et al., 2018, Developmental Cell and Development). More excitingly, evidence from postimplantation marmoset embryos reveals hallmarks of canonical and non-canonical WNT signalling (Bergmann et al, unpublished data). Further to this, the majority of our knowledge surrounding WNT signalling in embryonic stem cells is owed to research in naïve pluripotent stem cells from mouse embryos. Current culturing regeimes to propagate human naïve ES cells require WNT inhibition, in contrast where WNT activation permits long term self-renewal of mouse ES cells. This fundamental difference reveals a sharp divergence in human and mouse preimplantation development and thus, requires a more in-depth investigation.Here, I aim to dissect the roles of the canonical WNT signalling pathway throughout early human embryogenesis using stem cell models and embryos. This will be investigated using RT-qPCR, immunofluorescence, ChIP-seq, single-cell RNA sequencing, synthetic mRNA overexpression, siRNA-mediated knockdown and CRISPR-CAS9 targeted mutagenesis.