The roles of cell polarity and polarity proteins in cell fate decisions and epithelial development during primitive endoderm formation.

细胞极性和极性蛋白在原始内胚层形成过程中细胞命运决定和上皮发育中的作用。

• 批准号: BB/G012393/1
• 负责人: Berenika Plusa
• 金额: $ 53.91万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FG012393%2F1
• 关键词: roles; cell; polarity; proteins; fate

Early development of the mammalian embryo involves about six cell divisions from the one-cell stage (zygote) until the time it implants into the uterus (around 100 cells). Originally all cells (blastomeres) within the embryo are the same and have equal potential to form any of the cell types in the future foetus. From around the 8-cell stage, a process of differentiation begins and blastomeres gradually become committed to one of the first three cell lineages: the trophectoderm (TE) and the primitive endoderm (PrE), which both contribute to the placenta, and the pluripotent epiblast (EPI), which gives rise to the foetus. At the blastocyst stage, the TE consists of a single layer of cells ('epithelium') enclosing both a fluid-filled cavity and an adjacent inner cell mass (ICM). By the late blastocyst stage, the PrE appears as a noticeable layer of cells on the surface of the ICM lining the cavity, with deeper cells comprising the epiblast. TE and PrE form extra-embryonic tissues required for nutrient exchange and for the induction of the body axis of the embryo. Both ICM and EPI are sources of continually self-renewing embryonic stem cells, which can be induced to differentiate into specific cell types such as cardiac, neural or endocrine lineages in culture and thus offer enormous prospects in the field of regenerative medicine. Therefore, extending our knowledge of the mechanisms underlying cell lineage specification and cellular reprogramming during normal development is not only crucial for understanding mammalian development but also for the advance of cell-based therapies of such diseases as diabetes or Parkinson's disease. Preimplantation mouse embryos provide an excellent model for studying lineage specification in a three-dimensional context. The development of TE and ICM has been extensively studied and it was shown that cell polarity and the associated asymmetric (differentiative) divisions of the 8-cell stage and 16-cell stage blastomeres are critical to differentiation of these two lineages. Thus far, however, segregation of PrE and EPI has received comparatively little attention. The work proposed here aims to understand the role of cell polarity and polarity proteins during PrE vs. EPI specification. We plan to investigate the process of epithelialisation during PrE formation and to test whether interfering with a cell's ability to polarise can influence its contribution to PrE or EPI. Our research will help to extend our knowledge of the mechanisms underlying lineage specification during normal development. Furthermore, it will help to define the optimal environments for maintaining cell-type stability and inducing effective differentiation of pluripotent stem cells.

哺乳动物胚胎的早期发育包括大约六个细胞分裂，从单细胞期(受精卵)到植入子宫(大约100个细胞)。最初，胚胎内的所有细胞(卵裂球)都是相同的，并具有相同的潜力，可以在未来的胎儿中形成任何类型的细胞。从大约8-细胞期开始，一个分化的过程开始，卵裂球逐渐成为前三个细胞谱系之一：滋养外胚层(TE)和原始内胚层(PRE)，它们都有助于胎盘，以及多能上胚层(EPI)，它产生胎儿。在囊胚期，TE由单层细胞(“上皮”)组成，包围着一个充满液体的空腔和邻近的内细胞团(ICM)。到胚泡晚期，Pre出现在腔内ICM表面的一层明显的细胞层上，较深的细胞组成上胚层。TE和PRE形成胚胎外组织，是进行营养交换和诱导胚胎体轴所必需的。ICM和EPI都是不断自我更新的胚胎干细胞的来源，在培养过程中可以诱导其分化为特定的细胞类型，如心脏、神经或内分泌谱系，因此在再生医学领域具有巨大的前景。因此，扩大我们对正常发育过程中潜在的细胞谱系指定和细胞重编程的机制的了解，不仅对于理解哺乳动物的发育，而且对于糖尿病或帕金森病等疾病的基于细胞的治疗的进展至关重要。植入前的小鼠胚胎为在三维环境中研究谱系特征提供了一个很好的模型。TE和ICM的发育已经得到了广泛的研究，研究表明，细胞的极性以及与之相关的8-细胞期和16-细胞期卵裂球的不对称(分化)分裂是这两个谱系分化的关键。然而，到目前为止，Pre和EPI的分离相对较少受到关注。这里提出的工作旨在了解细胞极性和极性蛋白质在PRE和EPI规范中的作用。我们计划研究形成前的上皮化过程，并测试干扰细胞的极化能力是否会影响其对Pre或EPI的贡献。我们的研究将有助于扩展我们对正常发育过程中潜在的谱系指定的机制的了解。此外，这将有助于确定维持细胞类型稳定和诱导多能干细胞有效分化的最佳环境。

项目成果

Atypical protein kinase C couples cell sorting with primitive endoderm maturation in the mouse blastocyst.

非典型蛋白激酶伴侣在小鼠胚泡中与原始内胚层成熟的细胞分类。

• DOI: 10.1242/dev.093922
• 发表时间: 2013-11
• 期刊: Development (Cambridge, England)
• 作者: Saiz N;Grabarek JB;Sabherwal N;Papalopulu N;Plusa B
• 通讯作者: Plusa B

Primitive endoderm formation is dependent on atypical Protein Kinase C activity

原始内胚层的形成取决于非典型蛋白激酶 C 活性

• 作者: Berenika Plusa (Co-Author)

Positional information provided by polarity influences expression of lineage specific

极性提供的位置信息影响谱系特异性的表达

• 作者: Berenika Plusa (Co-Author)

Sorting out cell fate in the mouse blastocyst

分选小鼠囊胚中的细胞命运

• 作者: Berenika Plusa (Author)

The embryonic microenvironment influences the developmental potential ofepiblast and primitive endoderm precursors in the mouse embryo.

胚胎微环境影响小鼠胚胎中外胚层和原始内胚层前体的发育潜力。

• 作者: Berenika Plusa (Co-Author)