Cell surface glycosylation regulation of stem cell fate decisions

当身体在发育过程中形成时，产生每个器官的细胞会接收各种化学、机械和电信号，帮助它们决定要成为什么类型的成熟细胞。一些化学和机械信号由分子传递，这些分子可以自由移动或结合到细胞或表面上，这些分子将自己附着到嵌入在发育细胞外部的传感器分子上。细胞外表面覆盖着糖，但这些糖在帮助细胞获得和解释它们在发育过程中接收的信号方面的作用仍然知之甚少。首席研究员的实验室以前设计了一种新的方法来研究细胞表面，并利用它来确定糖在调节大脑形成中的新作用。本项目将阐明细胞表面不同类型的糖如何影响大脑发育的关键决策点，为影响大脑形成和功能的关键过程提供新的线索。由于这些研究中发现的细胞表面成分也存在于大脑以外的其他器官上，因此这项研究的结果可能揭示了细胞表面糖影响全身许多器官发育的重要一般机制。该项目包括通过社区外展计划为K-12学生提供有趣和引人入胜的多学科科学体验，以鼓励未来的科学家。这些举措旨在鼓励和增强青年人的能力，使他们成为科学家，能够联合收割机综合各种科学学科的方法，加深我们对生物发展的理解。未分化的细胞遇到各种影响细胞命运的外部信号。外部信号与质膜蛋白结合，糖基化通过控制其配体亲和力和细胞表面停留时间在调节膜蛋白中起着至关重要的作用。尽管糖基化的重要性，其在细胞命运决定中的作用一直未被充分认识和研究。本项目的目标是了解糖基化如何影响神经干细胞的神经发生和星形命运决定。以前的研究设计了一种新的方法来确定细胞的命运，也反映了细胞表面糖基化，并发现糖基化调节神经干细胞的命运决定。还鉴定了关键酶[Mgat 5（与星形发生相关）和Mgat 3（与神经发生相关）]和细胞表面蛋白的不同命运特异性模式。目前的研究测试的一般假设，Mgat 5和Mgat 3活动的平衡是命运潜力的关键决定因素，并调节细胞表面蛋白与细胞外配体的相互作用。使用体内和体外实验测试三个更具体的假设：（1）Mgat 5活性促进星形发生，（2）Mgat 3防止星形发生并促进神经发生，（3）由于Mgat 5和Mgat 3的活性，神经源性和星形细胞在细胞表面蛋白功能上不同。预计这些研究将揭示一个关键的调节机制，细胞利用响应无数的细胞外信号，影响他们的命运选择。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

As the body forms during development, the cells that generate each organ receive a wide array of chemical, mechanical, and electrical signals that help them decide what types of mature cells to become. Some chemical and mechanical signals are conveyed by molecules, either freely-traveling or bound to a cell or a surface, that attach themselves to sensor molecules embedded on the outside of the developing cells. This cell outer surface is covered in sugars, but the role these sugars play in helping cells acquire and interpret the signals they receive during development remains poorly understood. The Principal Investigator's laboratory previously devised a novel way to study the cell surface, and used it to identify a new role for sugars in regulating brain formation. The present project will elucidate how the different types of sugars on the cell surface influence key decision points in brain development, shedding new light on crucial processes that affect brain formation and function. Since the cell surface components identified in these studies are also present on other organs besides the brain, the results of this research may reveal important general mechanisms through which cell surface sugars impact the development of many organs throughout the body. This project includes initiatives to encourage tomorrow’s scientists by providing a fun and engaging multi-disciplinary science experience for K-12 students through a community outreach program. These initiatives aim at encouraging and empowering young people to become scientists who can combine approaches from a variety of scientific disciplines to deepen our understanding of biological development. Undifferentiated cells encounter a variety of external signals that impact cell fate. External signals bind to plasma membrane proteins, and glycosylation plays a vital role in regulating membrane proteins by controlling their ligand affinity and cell surface residence time. Despite the importance of glycosylation, its role in cell fate decisions has been under-appreciated and under-studied. The goal of this project is to understand how glycosylation impacts neurogenic and astrogenic fate decisions of neural stem cells. Previous research devised a novel way to determine cell fate that also reflects cell surface glycosylation, and found that glycosylation regulates neural stem cell fate determination. Key enzymes [Mgat5 (associated with astrogenesis) and Mgat3 (associated with neurogenesis)] and distinct fate-specific patterns of cell surface proteins were also identified. The present research tests the general hypothesis that the balance of Mgat5 and Mgat3 activities is a critical determinant of fate potential, and regulates cell surface protein interactions with extracellular ligands. Three more specific hypotheses are tested using in-vivo and in-vitro experiments: (1) Mgat5 activity promotes astrogenesis, (2) Mgat3 prevents astrogenesis and promotes neurogenesis, (3) neurogenic and astrogenic cells differ in cell surface protein function due to the activities of Mgat5 and Mgat3. It is expected that these studies will reveal a crucial regulatory mechanism cells utilize to respond to the myriad extracellular signals that impact their fate choices.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.