Role of Connexin 43 in Cranial Neural Crest Cell Differentiation

连接蛋白 43 在颅神经嵴细胞分化中的作用

• 批准号: 576458-2022
• 负责人: Willmore, KatherineKE
• 金额: $ 1.82万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Alliance Grants
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=743440
• 关键词: Role; Connexin; 43; Cranial; Neural

Much of the face and skull is formed by a special type of stem cells, called cranial neural crest cells (CNCCs). These cells arise from the developing brain and migrate into the forming head where they change identity, or differentiate, into a variety of cell types such as bone and cartilage cells and neurons. Through their contribution to the sensory organs and jaws, the origin of CNCCs in vertebrates is considered the main driver of predatory feeding evolution. Given the functional importance of the structures formed by CNCCs, proper differentiation of these cells is crucial, and is coordinated by cell-cell communication. Cells can communicate through gap junctions, which are small channels between adjacent cells formed by proteins called connexins. The most common gap junction protein is connexin 43 (Cx43), and this protein is expressed in CNCCs and is important for their migration to the developing head. However, the role of Cx43 in CNCC differentiation remains obscure. Therefore, the main objective of our collaboration is to determine the role of Cx43 in CNCC differentiation using mouse and chick models. To accomplish this objective, we have developed a mouse model wherein Cx43 is removed specifically from neural crest cells, known here as Cx43cKO. As expected, skull shape is altered in Cx43cKO mice, and these shape changes are localized to regions derived from CNCCs. To determine the role of Cx43 in CNCC differentiation, we will compare gene expression within single cells of CNCC origin between Cx43cKO and control mice, providing a list of genes involved in this cellular process. To understand how these target genes mediate CNCC differentiation, we will use the chick model where we can experimentally manipulate genes of interest to rapidly evaluate gene function. These studies will provide answers to fundamental questions related to stem cell differentiation, and, more broadly, skull development and evolution, helping to put Canada at the forefront of this vibrant and expanding scientific field. Additionally, trainees will gain valuable professional and technical skills that will position them for successful employment in academia and industry, enhancing Canada's economy.

面部和头骨的大部分是由一种特殊类型的干细胞形成的，称为颅神经嵴细胞（CNCC）。这些细胞产生于发育中的大脑，并迁移到正在形成的头部，在那里它们改变身份或分化成多种细胞类型，例如骨细胞、软骨细胞和神经元。通过对感觉器官和下颌的贡献，脊椎动物中 CNCC 的起源被认为是掠食性进食进化的主要驱动力。鉴于 CNCC 形成的结构的功能重要性，这些细胞的适当分化至关重要，并通过细胞间通讯进行协调。细胞可以通过间隙连接进行通信，间隙连接是相邻细胞之间由称为连接蛋白的蛋白质形成的小通道。最常见的间隙连接蛋白是连接蛋白 43 (Cx43)，该蛋白在 CNCC 中表达，对于 CNCC 迁移到发育中的头部非常重要。然而，Cx43 在 CNCC 分化中的作用仍然不清楚。因此，我们合作的主要目标是使用小鼠和雏鸡模型确定 Cx43 在 CNCC 分化中的作用。为了实现这一目标，我们开发了一种小鼠模型，其中 Cx43 被特异地从神经嵴细胞中去除，此处称为 Cx43cKO。正如预期的那样，Cx43cKO 小鼠的头骨形状发生了改变，并且这些形状变化局限于源自 CNCC 的区域。为了确定 Cx43 在 CNCC 分化中的作用，我们将比较 Cx43cKO 和对照小鼠之间 CNCC 起源的单细胞内的基因表达，提供参与此细胞过程的基因列表。为了了解这些靶基因如何介导 CNCC 分化，我们将使用小鸡模型，在该模型中我们可以通过实验操作感兴趣的基因来快速评估基因功能。这些研究将为干细胞分化以及更广泛的头骨发育和进化相关的基本问题提供答案，有助于使加拿大处于这个充满活力和不断扩展的科学领域的前沿。此外，学员将获得宝贵的专业和技术技能，这将使他们能够在学术界和工业界成功就业，从而促进加拿大经济的发展。