This project addresses fundamental questions in developmental biology using the developing leg of Drosophila melanogaster as the model system. In addition to having antero-posterior (AP) and dorso- ventral (DV) axes, the mature leg, as all appendages, also has a proximo-distal (PD) axis. Unlike the AP and DV axes, the PD axis must form de novo, within each thoracic hemisegment of a developing embryo. In the fly, the leg primordia are first identifiable as a cluster of ~30 cells that express the homeodomain-encoding Distalless (Dll) gene. By the end of larval development, the presumptive leg has ~20,000 cells and several defined domains along the PD axis. The goal of this project is understand how these cells obtain their positional information. Generally, a 'bottom-up' approach is used, in which cis-regulatory modules (CRMs) that drive the expression of PD genes are dissected in detail, to identify the upstream inputs that control their activities. In ths way, a network of CRM and gene activities will be generated. In the next funding period, particular attention will be given to 1) the most proximal PD domain, which co-expresses homothorax (hth), which encodes a homeodomain transcription factor, and teashirt (tsh), which encodes a Zn-finger nuclear factor and 2) the most distal PD domain, which is further elaborated due to the activities of the Epidermal Growth Factor Receptor pathway. In addition, the role of two 'ventral-identity' factors, encoded by the Drosophila homologs of vertebrate Sp8, dSp1 and buttonhead (btd), will be investigated, using both a CRM-centric and target gene approaches. Altogether, these experiments will lead to a better understanding of how positional information is generated in dividing cells, using transcription factors and signaling pathways that are conserved from flies to man.

Public Health Relevance

This project uses state-of-the-art genetic and molecular methods in the fruit fly, Drosophila melanogaster, to understand how dividing cells become different from each other within a developing tissue. Such knowledge is important for understanding the causes of many human diseases, including cancers and birth defects.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM058575-17
Application #
8815208
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
1999-01-01
Project End
2018-11-30
Budget Start
2015-01-01
Budget End
2015-11-30
Support Year
17
Fiscal Year
2015
Total Cost
$327,685
Indirect Cost
$115,685
Name
Columbia University (N.Y.)
Department
Biochemistry
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Newcomb, Susan; Voutev, Roumen; Jory, Aurelie et al. (2018) cis-regulatory architecture of a short-range EGFR organizing center in the Drosophila melanogaster leg. PLoS Genet 14:e1007568
Requena, David; Álvarez, Jose Andres; Gabilondo, Hugo et al. (2017) Origins and Specification of the Drosophila Wing. Curr Biol 27:3826-3836.e5
Voutev, Roumen; Mann, Richard S (2017) Bxb1 phage recombinase assists genome engineering in Drosophila melanogaster. Biotechniques 62:37-38
Voutev, Roumen; Mann, Richard S (2016) Streamlined scanning for enhancer elements in Drosophila melanogaster. Biotechniques 60:141-4
Zhou, Tianyin; Shen, Ning; Yang, Lin et al. (2015) Quantitative modeling of transcription factor binding specificities using DNA shape. Proc Natl Acad Sci U S A 112:4654-9
Riley, Todd R; Lazarovici, Allan; Mann, Richard S et al. (2015) Building accurate sequence-to-affinity models from high-throughput in vitro protein-DNA binding data using FeatureREDUCE. Elife 4:
Abe, Namiko; Dror, Iris; Yang, Lin et al. (2015) Deconvolving the recognition of DNA shape from sequence. Cell 161:307-18
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
Oh, Hyangyee; Slattery, Matthew; Ma, Lijia et al. (2013) Genome-wide association of Yorkie with chromatin and chromatin-remodeling complexes. Cell Rep 3:309-18

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