Animal development depends on the successive refinement of cell fates and cell potentials. Embryonic stem cells, for example, are pluripotent but their descendents gradually take on more specific fates depending on the extracellular cues they perceive and intrinsic factors they express. Understanding this process at a mechanistic level is important for eventually harnessing the potential of stem cells for medicine, as well as for understanding many diseases, such as cancers, where this process fails to be properly regulated. In this project, the model system to be investigated is appendage specification in the fruit fly, Drosophila melanogaster. One goal is to understand, at a molecular level, how the initial leg and wing primordia become established in the early embryo. A second goal is to characterize the mechanism by which cis-regulatory enhancer elements integrate signaling and transcription factor inputs during the formation of the proximal- distal axis in the leg. A third goal is to investigate how the Epidermal Growth Factor pathway establishes positional information in the distal-most segments of the leg. Together, these Aims will provide significant insights into how appendages are first specified to how final positional information in the leg is achieved.

Public Health Relevance

This project addresses fundamental processes during animal development, in particular, how cells gradually restrict their potentials as development proceeds. Stem cells, for example, are pluripotent, but some of their descendents have more limited potentials. When this process is not properly regulated, developmental defects and cancers can result.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM058575-16
Application #
8599778
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
1999-01-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
16
Fiscal Year
2014
Total Cost
$308,551
Indirect Cost
$115,051
Name
Columbia University (N.Y.)
Department
Biochemistry
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Agelopoulos, Marios; McKay, Daniel J; Mann, Richard S (2014) cgChIP: a cell type- and gene-specific method for chromatin analysis. Methods Mol Biol 1196:291-306
Slattery, Matthew; Voutev, Roumen; Ma, Lijia et al. (2013) Divergent transcriptional regulatory logic at the intersection of tissue growth and developmental patterning. PLoS Genet 9:e1003753
Li, Xin; Erclik, Ted; Bertet, Claire et al. (2013) Temporal patterning of Drosophila medulla neuroblasts controls neural fates. Nature 498:456-62
Agelopoulos, Marios; McKay, Daniel J; Mann, Richard S (2012) Developmental regulation of chromatin conformation by Hox proteins in Drosophila. Cell Rep 1:350-9
Estella, Carlos; Voutev, Roumen; Mann, Richard S (2012) A dynamic network of morphogens and transcription factors patterns the fly leg. Curr Top Dev Biol 98:173-98
Giorgianni, Matt W; Mann, Richard S (2011) Establishment of medial fates along the proximodistal axis of the Drosophila leg through direct activation of dachshund by Distalless. Dev Cell 20:455-68
Estella, Carlos; Mann, Richard S (2010) Non-redundant selector and growth-promoting functions of two sister genes, buttonhead and Sp1, in Drosophila leg development. PLoS Genet 6:e1001001
Joshi, Rohit; Sun, Liping; Mann, Richard (2010) Dissecting the functional specificities of two Hox proteins. Genes Dev 24:1533-45
Crickmore, Michael A; Ranade, Vikram; Mann, Richard S (2009) Regulation of Ubx expression by epigenetic enhancer silencing in response to Ubx levels and genetic variation. PLoS Genet 5:e1000633
Peng, H Wayne; Slattery, Matthew; Mann, Richard S (2009) Transcription factor choice in the Hippo signaling pathway: homothorax and yorkie regulation of the microRNA bantam in the progenitor domain of the Drosophila eye imaginal disc. Genes Dev 23:2307-19

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