One fundamental property of biological systems is the coordination of cellular proliferation with the regulation of cell size. This coordination ensures that cells grow to a minimum size prior to dividing and functions as a checkpoint to prevent unrestricted proliferation. While it is not fully understood how cells measure their size, it has lng been appreciated that the determination of cell size is coupled to the ratio of genomic DNA to cytoplasmic volume. This indicates that there exists a biological mechanism for measuring this nucleo-cytoplasmic (N:C) ratio, but the components of this mechanism are currently unknown. This research project proposes to use the study of the maternal to zygotic transition of the fruit fly Drosophila melanogaster as a model to understand further the mechanism of N:C ratio measurement. Early embryos couple the transition from maternal to zygotic control of development to the measurement of the N:C ratio. This transition results in global changes in embryonic gene expression, stemming, in part, from coordinated activities of both translation-regulatory and chromatin modifying mechanisms. However, a precise account of the mechanism underlying this coordination has been hampered by a paucity of mutants that specifically disrupt this process. The proposed investigation will examine the function of two recently identified Drosophila mutants with potential defects in N:C ratio measurement (dfmr1/capr and valois), and use these factors as a molecular entry point to test two models for quantifying the N:C ratio. I propose to investigate the mechanisms regulating the measurement of the N:C ratio in early Drosophila embryos by exploring the cause of the mutant phenotypes of valois and dfmr1/capr. Since valois and dfmr1 have been shown to interact with additional factors, I propose to test whether loss of function for these partners uncovers additional mutants with putative defects in N:C ratio measurement. With these mutants in hand, I will measure the effect of these defects on the temporal control of zygotic gene activation, using an assay developed in the Wieschaus lab that distinguishes N:C ratio-dependent and -independent effects. Finally, I will test whether mutants of this class interact physically and genetically in order to understand further the regulatory logic underlying this phenotypic class of mutants. I propose two models for quantification of the N:C ratio by translation- or chromatin-coupled mechanisms. By further investigation of dfmr1/capr-dependent translational control of maternal mRNA expression, and valois-dependent chromatin modification, I will examine two candidate mechanisms for measuring the N:C ratio. This project will therefore expand the understanding both of early developmental regulatory systems, and of a fundamental mechanism for measuring cellular size.

Public Health Relevance

The measurement of cell size is a fundamental biological process that underlies tissue homeostasis, functioning as a checkpoint to prevent unregulated cell growth;but the mechanism whereby cells monitor their size is poorly understood. This research will study one sizing mechanism, the nucleo- cytoplasmic ratio, in the context of the embryo, when cell size measurement regulates a major transition during early development. This work aims to define a fundamental mechanism for monitoring cell size and coordinating the early events of embryonic development.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F05-P (20))
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Ravindranath, Neelakanta
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Princeton University
Schools of Arts and Sciences
United States
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Hannon, Colleen E; Blythe, Shelby A; Wieschaus, Eric F (2017) Concentration dependent chromatin states induced by the bicoid morphogen gradient. Elife 6:
Blythe, Shelby A; Wieschaus, Eric F (2016) Establishment and maintenance of heritable chromatin structure during early Drosophila embryogenesis. Elife 5:
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Blythe, Shelby A; Wieschaus, Eric F (2015) Zygotic genome activation triggers the DNA replication checkpoint at the midblastula transition. Cell 160:1169-81
Di Talia, Stefano; She, Richard; Blythe, Shelby A et al. (2013) Posttranslational control of Cdc25 degradation terminates Drosophila's early cell-cycle program. Curr Biol 23:127-32