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

如何整合命运：阐明早期人类胚胎发生中 WNT 信号传导的上下文相关分子机制

基本信息

批准号：
2117379
负责人：
金额：
--
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2117379
关键词：
How integrate fate explicating context

项目摘要

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from postimplantation marmoset embryos reveals hallmarks of canonical and non-canonical WNT signalling (Bergmann et al, unpublished data).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.

WNT信号通路在胚胎发育、干细胞动力学和癌症中发挥着一系列关键作用（Clevers，2006，Nature）。虽然发育和癌症生物学是同一枚硬币的两面，但WNT信号通路目前是一个激烈的研究领域。然而，虽然一些机制已经被描述，但我们在自己物种的发展背景下的理解需要复杂的询问。跨物种转录组学分析揭示了WNT信号传导在人类和猴植入前胚胎发育中的先前未被认识到的作用（Boroviak等人，2015; Stirparo等人，2018年，《细胞与发育》（Developmental Cell and Development）。更令人兴奋的是，来自植入后绒猴胚胎的证据揭示了经典和非经典WNT信号传导的特征（Bergmann等人，未发表的数据）。除此之外，我们对胚胎干细胞中WNT信号传导的大部分了解都归功于对来自小鼠胚胎的幼稚多能干细胞的研究。目前繁殖人幼稚ES细胞的培养程序需要WNT抑制，相反，WNT活化允许小鼠ES细胞的长期自我更新。这种根本的差异揭示了人类和小鼠植入前发育的急剧分化，因此，需要更深入的investigation. In这里，我的目标是解剖的经典WNT信号通路的作用，在整个早期人类胚胎发育干细胞模型和胚胎。这将使用RT-qPCR、免疫荧光、ChIP-seq、单细胞RNA测序、合成mRNA过表达、siRNA介导的敲减和CRISPR-CAS 9靶向诱变进行研究。