Proper development of all multi-cellular organisms requires not only correct spatial control of cellular interactions, but also correct timing of specific gene expression programs during development. Altering the timing of many developmental processes can significantly affect an animals final body size, reproductive ability and ageing. In insects, timing of developmental transitions, i.e. molting and metamorphosis, is mediated by 20-hydroxyecdysone (20E), a small circulating lipophilic steroid hormone that binds to and activates transcription factors of the nuclear receptor superfamily. Although the genetic hierarchy that controls responses to 20E has received considerable attention, little is presently known about mechanisms that control the timing of hormone production and its release. In this proposal we will determine how prothoraciotropic hormone, a peptide released from neurons that innervate the prothoracic gland (PGs) control hormone production and release.
In aim 1 we will determine when the PG cells receive PTTH signals and what regulates their competence to do so.
In aim 2 we will characterize additional upstream and downstream inputs that regulate PTTH signaling through the receptor tyrosine kinase Torso. Of particular interest is to determine if the PTTH ligand processing is required for PTTH signaling and if PKC, PLC and the IP3 receptor, contribute to PTTH signaling in Drosophila and how their activity is coupled to Torso activation.
In aim 3, we will identify key transcriptional control elements in the regulatory regions of the ecdysone biosynthetic enzymes phm, dib and spookier, in order to learn how PTTH signals regulate ecdysone production.
In aim4 we will use genetic studies and imaging methods to test the hypothesis that, contrary to present beliefs, release of ecdysone from the prothoracic gland during the metamorphic molt is a vesicle mediated process stimulated by PTTH. Impact on human health: In humans, a major developmental transition involving steroid hormones takes place as adolescents acquire sexual maturity. This transition is also controlled by a neuropeptide signal in conjunction with nutritional and metabolic cues, although little is presently known about how these signals are integrated to time the transition appropriately. The studies described here will help identify basic molecular programs that control developmental transitions and thereby provide a paradigm for understanding how these processes might be regulated in vertebrates including humans. In addition these studies will provide a new understanding of how steroid hormones are released from endocrine cells.

Public Health Relevance

The studies described here will help identify basic molecular programs that regulate steroid hormone production and secretion in insects. Since related developmental transitions and steroid release mechanisms occur in many organisms, including humans, this work will provide a paradigm for understanding how different steroidogenic regulatory cues are integrated by the neuroendocrine circuit to control development.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM093301-03
Application #
8319513
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Maas, Stefan
Project Start
2010-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$357,344
Indirect Cost
$108,982
Name
University of Minnesota Twin Cities
Department
Genetics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Ou, Qiuxiang; Zeng, Jie; Yamanaka, Naoki et al. (2016) The Insect Prothoracic Gland as a Model for Steroid Hormone Biosynthesis and Regulation. Cell Rep 16:247-62
Danielsen, E Thomas; Moeller, Morten E; Yamanaka, Naoki et al. (2016) A Drosophila Genome-Wide Screen Identifies Regulators of Steroid Hormone Production and Developmental Timing. Dev Cell 37:558-70
Fresán, Ujué; Cuartero, Sergi; O'Connor, Michael B et al. (2015) The insulator protein CTCF regulates Drosophila steroidogenesis. Biol Open 4:852-7
Komura-Kawa, Tatsuya; Hirota, Keiko; Shimada-Niwa, Yuko et al. (2015) The Drosophila Zinc Finger Transcription Factor Ouija Board Controls Ecdysteroid Biosynthesis through Specific Regulation of spookier. PLoS Genet 11:e1005712
Ghosh, Arpan C; Shimell, MaryJane; Leof, Emma R et al. (2015) UPRT, a suicide-gene therapy candidate in higher eukaryotes, is required for Drosophila larval growth and normal adult lifespan. Sci Rep 5:13176
Yamanaka, Naoki; Marqués, Guillermo; O'Connor, Michael B (2015) Vesicle-Mediated Steroid Hormone Secretion in Drosophila melanogaster. Cell 163:907-19
Moeller, Morten E; Danielsen, E Thomas; Herder, Rachel et al. (2013) Dynamic feedback circuits function as a switch for shaping a maturation-inducing steroid pulse in Drosophila. Development 140:4730-9
Yamanaka, Naoki; Rewitz, Kim F; O'Connor, Michael B (2013) Ecdysone control of developmental transitions: lessons from Drosophila research. Annu Rev Entomol 58:497-516
Lin, Suewei; Marin, Elizabeth C; Yang, Ching-Po et al. (2013) Extremes of lineage plasticity in the Drosophila brain. Curr Biol 23:1908-13
Yamanaka, Naoki; Romero, Nuria M; Martin, Francisco A et al. (2013) Neuroendocrine control of Drosophila larval light preference. Science 341:1113-6

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