The morphogen concept is central to developmental biology. Morphogen molecules form concentration gradients to provide positional information to a field of cells. This application will focus on experimental studies to advance the morphogen concept. The Drosophila morphogen gradient of Bicoid (Bcd) instructs anterior- posterior (AP) patterning by directly activating its downstream target genes in a concentration-dependent manner. Although the role of Bcd in AP patterning is well established, the regulatory network controlling this process is not fully understood. For example, several aspects critical to the operation and regulation of the Bcd gradient system, e.g., Bcd degradation, post-translational modifications, and Bcd gradient scaling within a species, remain virtually unknown at this time. The overall hypothesis of this application is that a regulatory network enables Bcd to respond to various inputs, both before and during the time of gradient formation, and at the time of its action as a transcriptional activator. These three layers of the regulatory network are investigated in three specific aims.
Aim 1 will study the mechanisms that regulate Bcd gradient formation by focusing on the role of MAP kinase (MAPK) and other regulators that control Bcd degradation.
Aim 2 will investigate the mechanisms that regulate the action of Bcd as an activator by focusing on its interaction with MAPK and the roles of post-translational modifications.
Aim 3 will investigate the mechanisms leading to a scaled Bcd gradient and will analyze the layer of regulation during oogenesis for its role in controlling the robust and scaled AP patterning later in embryos. The proposed study is based on strong preliminary studies and is made possible by a set of quantitative tools recently established in the lab. The proposed study will have powerful and sustained impact on our efforts to understand how morphogen gradients work and how developmental robustness is achieved. The proposed study is also important to human health because morphogens and MAPK signaling are fundamentally relevant to birth defects and, furthermore, the human homologue of a gene studied in this project has been implicated in otitis media, a leading cause of childhood deafness.

Public Health Relevance

The proposed work addresses a fundamental question in evolutionary and developmental biology, namely, how embryonic patterns are formed in a scaled and robust manner. It aims at dissecting the intricate regulatory network controlling pattern formation at a quantitative, systems level, information that will be fundamental to our ability to understand human genetic disorders that cause birth defects.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM101373-03
Application #
8691904
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
2012-08-15
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Liu, Junbo; Xiao, Yanyu; Zhang, Tongli et al. (2016) Time to move on: Modeling transcription dynamics during an embryonic transition away from maternal control. Fly (Austin) 10:101-7
Ma, Jun; He, Feng; Xie, Gengqiang et al. (2016) Maternal AP determinants in the Drosophila oocyte and embryo. Wiley Interdiscip Rev Dev Biol 5:562-81
Wu, Honggang; Manu; Jiao, Renjie et al. (2015) Temporal and spatial dynamics of scaling-specific features of a gene regulatory network in Drosophila. Nat Commun 6:10031
Cheung, David; Ma, Jun (2015) Probing the impact of temperature on molecular events in a developmental system. Sci Rep 5:13124
Liu, Junbo; Ma, Jun (2015) Modulation of temporal dynamics of gene transcription by activator potency in the Drosophila embryo. Development 142:3781-90
He, Feng; Wei, Chuanxian; Wu, Honggang et al. (2015) Fundamental origins and limits for scaling a maternal morphogen gradient. Nat Commun 6:6679
Cheung, David; Miles, Cecelia; Kreitman, Martin et al. (2014) Adaptation of the length scale and amplitude of the Bicoid gradient profile to achieve robust patterning in abnormally large Drosophila melanogaster embryos. Development 141:124-35
Liu, Junbo; Ma, Jun (2013) Dampened regulates the activating potency of Bicoid and the embryonic patterning outcome in Drosophila. Nat Commun 4:2968
He, Feng; Ma, Jun (2013) A spatial point pattern analysis in Drosophila blastoderm embryos evaluating the potential inheritance of transcriptional states. PLoS One 8:e60876
Liu, Junbo; Ma, Jun (2013) Uncovering a dynamic feature of the transcriptional regulatory network for anterior-posterior patterning in the Drosophila embryo. PLoS One 8:e62641

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