RUI: Role of the Endoplasmic Reticulum in mediating cell fate

多细胞生命发育过程中的一个重要步骤是细胞多样性的产生。具体来说，在多细胞生物中，细胞采用特定形状和功能的任务对成人身体计划的发育和组织的形成至关重要。这在多细胞生物中是一个高度保守的过程，涉及细胞分裂过程中因子的不平等或不对称分配，以使细胞采用不同的命运（例如成为神经元或成为皮肤）。在了解这些因素的分布方面已经取得了重大进展；然而，运动的调节和这些决定因素的选择以及它们如何传递给子细胞仍然知之甚少。首席研究员（PI）已经形成了一个模型，在细胞分裂过程中，细胞命运决定因子是由内质网（ER）组织和分布的，内质网是细胞中参与蛋白质折叠和分布的最大的隔间。该项目的目标是确定细胞分裂过程中细胞命运决定因素的运输和正确建立的途径，并表征内质网在细胞多样性产生中的作用。此外，该项目将提供机会，让不同的学生群体参与进来，并促进同伴指导，从而扩大对科学的参与。该项目的结果将有助于缩小关于细胞命运如何决定的知识差距，并为发育过程中细胞多样性的产生提供更广泛的理解。细胞多样性的产生是一个高度保守的机制，涉及细胞分裂过程中因子的不对称分配。在过去的30年里，已经确定了几种细胞命运决定因素，包括在有丝分裂过程中顶端或基部分裂导致子细胞采用不同细胞命运的细胞命运决定因素。尽管对参与细胞命运选择的因素有相当多的了解，但对有丝分裂过程中这些细胞命运决定因素沿分裂平面的运输、定位和组织知之甚少。来自PI实验室的初步数据发现，在黑腹果蝇胚胎发生过程中，高度保守的内质网（ER）整体膜蛋白Jagunal （Jagn）在前神经细胞中不对称地分裂。PI的核心假设是，jagn介导的内质网不对称分裂作为组织和转运转录机制的支架，涉及中枢神经系统中基底细胞命运决定因素的多样化。PI将通过使用超分辨率共聚焦显微镜检查黑腹果蝇幼虫大脑中的神经母细胞分裂来验证这一假设，并确定哪些细胞命运结果依赖于Jagn。PI的工作将加深我们对细胞命运选择的理解，并概述内质网在细胞多样性产生中的作用。这项研究由生物科学理事会分子和细胞生物科学部的细胞动力学和功能集群资助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

A major step during development in multicellular life is the generation of cell diversity. Specifically, the task of cells adopting a specific shape and function is essential towards development of the adult body plan and formation of tissues in multicellular organisms. This is a highly conserved process among multicellular creatures and involves an unequal or asymmetric partitioning of factors during cell division to allow cells to adopt different fates (e.g. to become neurons or become skin). There has been significant progress in understanding the distribution of these factors; however, the regulation of movement and the selection of these determinants and how they are passed to daughter cells is still poorly understood. The Principal Investigator (PI) has formed a model in which cell fate-determining factors are organized and distributed during cell division by the Endoplasmic Reticulum (ER), the largest compartment in the cell involved in protein folding and distribution. The objectives of this project are to define a pathway for the transport and correct establishment of cell-fate determinants during cell division, and to characterize the role of the ER in the generation of cell diversity. In addition, the PI will provide opportunities to engage a diverse student population and promote peer mentorship, thereby broadening participating in science. The outcomes of the project will help close a gap of knowledge regarding how cell fate is determined, and to provide a broader understanding for the generation of cell diversity during development.The generation of cell diversity is a highly conserved mechanism and involves the asymmetric partitioning of factors during cell division. Over the past 30 years, several cell fate determinants have been identified, including cell fate determinants that are partitioned apically or basally during mitosis leading to the daughter cells adopting different cell fates. Despite the considerable knowledge regarding the factors involved in cell fate selection, there is little known regarding the transport, localization, and organization of these cell fate determinants along the division plane during mitosis. Preliminary data from the PI’s laboratory identified the highly conserved Endoplasmic Reticulum (ER) integral membrane protein, Jagunal (Jagn) as being partitioned asymmetrically in pro-neural cells during Drosophila melanogaster embryogenesis. The PI’s central hypothesis is that the Jagn-mediated asymmetric division of the ER acts as a scaffold for organization and transport of transcriptional machinery involving the basal cell fate determinants towards the diversification of cell types in the central nervous system. The PI will test this hypothesis in vivo by examining neuroblast division in the Drosophila melanogaster larval brain by means of super-resolution confocal microscopy, and determine which cell fate outcomes are dependent on Jagn. The PI’s work will deepen our understanding of cell fate selection and outline the role of the ER in the generation of cell diversity.This research is funded by the Cellular Dynamics and Function cluster in the Division of Molecular and Cellular Biosciences in the Directorate of Biological Sciences.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.