CAREER: Asymmetric ER partitioning as a pathway for cell fate specification

San Francisco State University, San Francisco CA

Investigators

Abstract

This proposal addresses an important problem in multicellular organisms; namely cellular diversity. Cellular diversity is achieved through an asymmetric cell division, in which two produced daughter cells have different fates. The mechanism that generates different cell fates, during division, can either be generated by the mother cells itself (intrinsic) or by factors outside of the cell (extrinsic). Development of the central nervous system (CNS) in multicellular organisms relies on both extrinsic and intrinsic factors that affect asymmetric cell divisions, but the nature of these factors are poorly understood. The goal of the proposed research is to define an intrinsic factor that leads to the production of daughter cells with different cellular fates. This work will be performed in the fruitfly, Drosophila melanogaster, which has served as an outstanding research model leading to many discoveries. Importantly, these discoveries in the fruitfly, has informed much of our knowledge involving the development of other multicellular organisms (including humans). The PI has preliminary data demonstrating an asymmetric partitioning during cell division of the Endoplasmic Reticulum (ER), a major and critical intrinsic component of the cell. The ER is partitioned unequally into one daughter cell prior to the subsequent division of a subset of cells that will eventually develop into the CNS of the adult fly. The central hypothesis is that the ER is partitioned asymmetrically for the establishment of key cues that dictate cellular fate. Experiments are designed that will provide new insight into the issue of the generation of cell diversity, a fundamental question in biology. On the broader scientific level, the proposed research will integrate research and education by promoting diversity in Science, Technology, Engineering and Math (STEM) field. This will be accomplished by the creation of a Biology Undergraduate Mentor Program (BUMP) and will utilize the technique of near-peer mentoring for the recruitment and retention of students within STEM majors. Furthermore, BUMP mentors and mentees will provide community service opportunities at a local elementary school addressing the national need for more STEM mentoring. The PI's long-term research goal is to investigate the mechanisms of cell asymmetry and identify the signal(s) responsible for determining cell fate. The goal of the proposed research is to define the pathway of inheritance involving cell fate determinants and identify novel targets involved in the their transport and partitioning using the model organism, Drosophila melanogaster. The central hypothesis is that the ER is partitioned asymmetrically due to the interaction of the highly conserved transmembrane protein Jagunal (Jagn) with the cell cortex and is responsible for the establishment of key cell fate determinants. The PI will be the first to investigate the role of Jagn in asymmetric cell division and has demonstrated that the asymmetric partitioning of the ER observed in the neural epithelia is Jagn dependent. The PI will employ both genetic and in vivo cytological approaches to investigate the role of Jagn on development and neural cell fate. In addition, the PI will involve undergraduate researchers to identify targets that interact with Jagn by performing a dominant modifier-based screen of the Drosophila genome towards control asymmetric ER partitioning during mitosis. The experiments set forth in this application will provide new insight into the larger issue of the generation of cell diversity and has the potential to open the field to new models of asymmetric divisions.