Control of precisely timed gene expression during notochord development by brachyury
Active Project Grant Awarded Last action
- Award ID
- R01GM149841
- Recipient
-
New York University UEI NX9PXMKW5KW8
- Awarding agency
-
National Institute of General Medical Sciences
National Institutes of Health, Department of Health and Human Services
- Obligated
- $1,288,000
Award facts
- Assistance listing
- 93.859 Biomedical Research and Research Training
- Completion date 58% complete
- Place of performance
- New York, NY 10010, USA
Award details come from USAspending.gov.
Description
- Abstract
- Precise temporal regulation of stage-specific gene expression is fundamental for the proper development of all organisms. Different molecular mechanisms that ensure the regionalized activation of gene expression, such as activator gradients or localized transcriptional repressors, have been elucidated in remarkable detail; however, the structural features of CIS-regulatory sequences that enable transcription factors to achieve the timely deployment of their downstream genes remain mostly unclear. The evolutionarily conserved transcription factor brachyury provides an example of a regulator that controls the spatial and temporal expression of a large number of genes, many of which are required for the development of the notochord. The notochord is the main feature shared by all chordate embryos, from tunicates to humans. During the early embryogenesis of all chordates, the notochord provides support and patterning signals to the developing body and is indispensable for patterning neural tube, endoderm, paraxial mesoderm, and the structures that they will form. In the tunicate ciona, an invertebrate chordate, brachyury is exclusively expressed in notochord cells, where IT controls the expression of hundreds of genes. Even though ciona brachyury (CI-BRA) is steadily transcribed and transported to the nuclei of the notochord cells throughout development, the genes downstream of CI-BRA exhibit a distinctive, temporally staggered onset. In an effort to identify the CIS-regulatory strategies responsible for the precise temporal regulation of notochord gene expression by CI-BRA, we have characterized several CIS-regulatory regions (AKA enhancers) that control the notochord expression of CI-BRA- downstream genes characterized by different temporal onsets. These studies have led US to formulate a working hypothesis that explains how brachyury controls its early-, middle- and late-onset target genes. This hypothesis will be tested through the following experimental approaches: the elucidation of the CIS-regulatory principles underlying the sequential activation of early-onset and middle-onset notochord genes directly controlled by CI-BRA (aim 1); the functional analysis of two transcription factors that activate expression of late- onset notochord genes (aim 2); the exploration of the role of transcriptional repressors in notochord development (aim 3). These studies will shed light on the modalities employed by a pivotal transcription factor to set the temporal context for developmental processes of widespread relevance, such as convergent extension and extracellular matrix secretion, and will provide the mechanistic framework that is needed to diagnose and prevent malformations and tumorigenesis associated with the multifaceted transcription factor brachyury.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $322,000 | |
| Amendment | $322,000 | |
| Amendment | $322,000 | |
| Original award | $322,000 |
Quick answers
Who received award R01GM149841?
R01GM149841 was awarded to New York University by National Institute of General Medical Sciences (National Institutes of Health) on July 5, 2024.
How much is award R01GM149841 worth?
$1,288,000 has been obligated on R01GM149841.
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