Investigating the role of transcription factor Sox17 in formation of the zebrafish left/right organiser.

在脊椎动物发育过程中，内脏器官的位置，如肝脏在右边，心脏和胰腺在左边，是由一个短暂的胚胎结构控制的，一般被称为左/右组织者，在斑马鱼中被称为库普弗囊泡（KV）。产生KV的祖细胞的形成依赖于转录因子sox 32，其也控制内胚层的形成。内胚层是脊椎动物胚胎内形成的三个主要胚层之一，并对呼吸道和胃肠道以及相关器官如肝脏和胰腺做出主要贡献。斑马鱼sox 32和sox 17是由祖先Sox 17的复制产生的，因此哺乳动物Sox 17是两者最接近的同源物。然而，这两个斑马鱼基因的功能如何相互反映和哺乳动物Sox 17需要进一步的调查。虽然内胚层和DFC命运都需要sox 32，但sox 17表达依赖于Sox 32功能，因此两种细胞身份是否直接依赖于Sox 32而不是下游靶点Sox 17尚不清楚。我以前的研究表明，Sox 17能够挽救sox 32缺陷胚胎中KV祖细胞的损失，但不能挽救内胚层。这表明Sox 32和Sox 17可能独立地起作用以指定这两种不同的细胞类型。我们将探索Sox 32和Sox 17是否以及如何独立或冗余地指定内胚层和KV祖细胞，以及这如何反映祖先Sox 17的功能。该项目将揭示KV如何形成的关键分子细节，从而实现脊椎动物的左/右模式。它将对理解Sox蛋白的功能产生重大影响，这些蛋白与一系列生物过程和疾病有关，它们的功能进化，并提供关于左/右模式缺陷（称为异位）遗传基础的关键信息。

The placement of internal organs during vertebrate development, such as liver on the right, and heart and pancreas on the left is governed by a transient embryonic structure generically referred to as the left/right organiser, which in zebrafish is named Kupffer's vesicle (KV). Formation of the progenitor cells that give rise to the KV is dependent on the transcription factor sox32, which also controls the formation of endoderm. Endoderm is one of three primary germ layers formed within the vertebrate embryo, and makes major contributions to the respiratory and gastrointestinal tracts and associated organs such as the liver and pancreas. Zebrafish sox32 and sox17 arose from duplication of ancestral Sox17, hence mammalian Sox17 is the closest homologue to both. However, how the function of these two zebrafish genes reflect each other and mammalian Sox17 requires further investigation. While sox32 is required for both endoderm and DFC fates, sox17 expression is dependent of Sox32 function, therefore whether both cell identities are directly dependent on Sox32 rather than downstream target Sox17 is unclear. My previous research has suggested that Sox17 is able to rescue the loss of KV progenitors but not endoderm in sox32-deficient embryos. This suggests that Sox32 and Sox17 may act independently to specify these two distinct cell types. We will explore if and how Sox32 and Sox17 act independently or redundantly to specify endoderm and KV progenitors, and how this reflects ancestral Sox17 function.This project will uncover key molecular details of how the KV forms, and thus how vertebrate left/right patterning is achieved. It will have major implications in understanding the function of Sox proteins that are implicated in a range of biological processes and diseases, their functional evolution, and provide key information on the genetic basis of left/right patterning defects known as heterotaxy.