The onset of development requires the restart of the cell cycle in the fertilized egg. The prerequisites for this are the completion of meiosis, the modified cell cycle used to produce haploid eggs and sperm, and the activation of DNA replication and mitosis in the zygote that results from fusion of sperm and egg. The meiotic cell cycle is under developmental control in oogenesis, with specific arrest and release points to permit oocyte differentiation and coordination between completion of meiosis and fertilization. In many organisms, rapid embryogenesis is made possible by a modified cell cycle that relies on maternal stockpiles and occurs in the absence of transcription and growth. These developmental strategies highlight the requirement for post-transcriptional regulation: translational activation of maternal pools of mRNAs as well as regulated proteolysis for the completion of meiosis, and translational regulation to drive the embryonic division cycles. Drosophila is an ideal model organism in which to identify the key regulatory mechanisms and genes that govern translational and proteolytic control of the meiotic and early embryonic cycles. Superb genetic and cell biological approaches permit identification and diagnosis of mutants defective in these cell cycles, and control genes most often are conserved in humans. Thus these studies will provide fundamental insights into regulatory defects leading to birth defects, infertility and cancer. Regulatory genes for the meiotic cell cycle will be recovered by cloning the genes affected in a collection of mutants with failures in the developmental control of meiosis, and a genomics screen will identify mRNAs translationally activated as oocytes progress into meiosis and complete meiosis. A meiotic form of the Anaphase Promoting Complex/Cyclosome, APC/CCort, controls proteolysis essential for the completion of meiosis in the egg. The specificity of APC/CCort will be investigated, with the identification of substrates and regulators from dominant suppressors that already have been isolated. The PAN GU (PNG) protein kinase complex regulates the early embryonic cycles by promoting translation of Cyclin B to drive mitosis. PNG also controls the transition from maternal to zygotic control of development later in embryogenesis by promoting the translation of SMAUG (SMG), which triggers the degradation of maternal mRNAs. The developmental regulation of PNG kinase will be deciphered, and the mechanism by which it promotes translation will be defined, particularly its relationship to the translational repressor PUMILIO (PUM). Additional targets of PNG and interacting proteins will be isolated.

Public Health Relevance

Development begins when sperm and egg fuse at fertilization, causing the completion of meiosis in the egg and the onset of cell division in the newly formed embryo. Birth defects and infertility result from failure to properly regulate meiosis and embryonic cell division. Our research will identify new regulatory proteins essential for the proper control of meiosis and the onset of development.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM039341-25
Application #
8492104
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Haynes, Susan R
Project Start
1988-02-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
25
Fiscal Year
2013
Total Cost
$391,216
Indirect Cost
$190,592
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Kronja, Iva; Yuan, Bingbing; Eichhorn, Stephen W et al. (2014) Widespread changes in the posttranscriptional landscape at the Drosophila oocyte-to-embryo transition. Cell Rep 7:1495-508
Reed, B H; Orr-Weaver, T L (1997) The Drosophila gene morula inhibits mitotic functions in the endo cell cycle and the mitotic cell cycle. Development 124:3543-53