The three aims of this project address the function of molecular asymmetries that occur very early in animal development, and the mechanisms by which they arise. Asymmetric cell division is essential for generation of cell-type diversity during differentiation and development. Failure o properly undergo asymmetric cell divisions can lead to defects in stem-cell renewal, tissue regeneration, and can contribute to carcinogenesis. We propose to use a near-ideal natural system, the early C. elegans embryo, to characterize the mechanisms of asymmetric distribution of cellular contents in specific blastomeres with modern genomic tools and analysis, followed by tests of function. Specifically, this proposal aims (1) to use blastomere-specific isolation, RNA- seq, and other high-throughput sequencing applications to comprehensively map RNA inheritance and transcriptional activity of seven invariant cell divisions in early C. elegans development, (2) to test the biological significance of asymmetric RNA segregation in development, and (3) to define the cis and trans-acting mechanisms required for asymmetric RNA segregation. To achieve these goals, we will also apply new approaches and technologies to the study of asymmetric segregation of cellular components. Our research plan is likely to identify cell-fate determinants and mechanisms that are generalizable to other systems, including humans.

Public Health Relevance

One of the earliest events in human development is the creation of asymmetry, or making one cell different from another. Generating asymmetry is important for the creation of different cell types during development, for example heart cells versus liver cells. This grant explores the molecular mechanisms that are behind the asymmetric distribution of cellular contents in the very earliest embryonic divisions and selected adult cell divisions. What we discover may help us understand human development, possibly leading to an increased understanding of birth defects and disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genomics, Computational Biology and Technology Study Section (GCAT)
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Hoodbhoy, Tanya
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Princeton University
Schools of Arts and Sciences
United States
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Tintori, Sophia C; Osborne Nishimura, Erin; Golden, Patrick et al. (2016) A Transcriptional Lineage of the Early C. elegans Embryo. Dev Cell 38:430-44
Saha, Shambaditya; Weber, Christoph A; Nousch, Marco et al. (2016) Polar Positioning of Phase-Separated Liquid Compartments in Cells Regulated by an mRNA Competition Mechanism. Cell 166:1572-1584.e16
Wiesenfahrt, Tobias; Berg, Janette Y; Osborne Nishimura, Erin et al. (2016) The function and regulation of the GATA factor ELT-2 in the C. elegans endoderm. Development 143:483-91
Osborne Nishimura, Erin; Zhang, Jay C; Werts, Adam D et al. (2015) Asymmetric transcript discovery by RNA-seq in C. elegans blastomeres identifies neg-1, a gene important for anterior morphogenesis. PLoS Genet 11:e1005117