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Mechanisms of signal integration in developmental control of organ size and tissue patterning

器官大小和组织模式发育控制中的信号整合机制

基本信息

批准号：
10669132
负责人：
Alexey Veraksa
金额：
$ 30.81万
依托单位：
UNIVERSITY OF MASSACHUSETTS BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-05 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669132
关键词：
Acute Address Animals Biochemical Biological Biological Assay Cells Computer Models DNA Binding Data Development Developmental Biology Developmental Process Disease Down-Regulation Drosophila genus Embryo Essential Genes Event Experimental Models Extracellular Signal Regulated Kinases Gene Expression Regulation Genetic Genetic Transcription Genetic study Goals Human Image Malignant Neoplasms Mesoderm Modeling Molecular Nature Neurodegenerative Disorders Nuclear Organ Size Pathologic Pathway interactions Pattern Phosphorylation Site Play Process Proteins Regulation Repression Research Role Signal Pathway Signal Transduction Site System Systems Biology Testing Time Tissues Transcription Repressor Work autism spectrum disorder cancer type cohort data-driven model design gastrulation gene repression human disease in vivo in vivo evaluation insight mathematical model neurocognitive disorder novel strategies optogenetics phosphoproteomics response sensor

项目摘要

PROJECT SUMMARY/ABSTRACT The proposed work will investigate transcriptional interpretation of signaling through the ERK pathway, which plays critical roles in animal development and is commonly deregulated in human diseases. We will use Drosophila as an experimental model that offers unrivaled opportunities for dissecting gene regulation by ERK signaling at multiple levels of biological organization, from specific ERK substrates to the whole embryo. Aim 1 focuses on Capicua (Cic), a transcriptional repressor that was discovered in Drosophila and has recently emerged as a key sensor of ERK activation in developmental and pathological contexts. We will identify functionally significant phosphorylation sites in Cic and investigate their effects on the ERK-dependent control of Cic protein stability, nuclear localization, and DNA binding. Aim 2 is designed to bridge the gap between genetic studies, which commonly identify only a handful of ERK substrates, and omics-level studies, which suggest that ERK functions through large substrate cohorts. We will evaluate these two scenarios using an already working combination of acute optogenetic perturbations, quantitative phosphoproteomics, and live imaging of functionally significant transcriptional responses to ERK signaling. Finally, Aim 3 will study transcriptional effects of ERK signaling, which commonly works by simultaneously activating some cell fates and repressing others. We will use quantitative optogenetic perturbations and live imaging to test the hypothesis that activating and repressing effects of ERK signaling require different levels of ERK activation. Our experimental tests of this hypothesis will address a key issue in developmental ERK signaling and will provide quantitative data needed for predictive computational modeling. Feasibility of the proposed work is supported by preliminary data that include functional characterization of Cic phosphosites (Aim 1), a phosphoproteomics approach for the in vivo discovery of ERK substrates (Aim 2), and an optogenetic approach to data-driven design of predictive computational models (Aim 3).

项目总结/文摘

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A dynamical model of growth and maturation in Drosophila.

DOI：
10.1073/pnas.2313224120
发表时间：
2023-12-05
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Tyson, John J.;Monshizadeh, Amirali;Shvartsman, Stanislav Y.;Shingleton, Alexander W.
通讯作者：
Shingleton, Alexander W.

Temporal integration of inductive cues on the way to gastrulation

原肠胚形成过程中诱导线索的时间整合

DOI：
10.1073/pnas.2102691118
发表时间：
2021
期刊：
Proceedings of the National Academy of Sciences
影响因子：
0
作者：
McFann, Sarah;Dutta, Sayantan;Toettcher, Jared E.;Shvartsman, Stanislav Y.
通讯作者：
Shvartsman, Stanislav Y.

Capicua is a fast-acting transcriptional brake.

DOI：
10.1016/j.cub.2021.05.061
发表时间：
2021-08-23
期刊：
Current biology : CB
影响因子：
0
作者：
Patel AL;Zhang L;Keenan SE;Rushlow CA;Fradin C;Shvartsman SY
通讯作者：
Shvartsman SY

Molecular mechanisms underlying cellular effects of human MEK1 mutations.

DOI：
10.1091/mbc.e20-10-0625
发表时间：
2021-04-19
期刊：
Molecular biology of the cell
影响因子：
3.3
作者：
Marmion RA;Yang L;Goyal Y;Jindal GA;Wetzel JL;Singh M;Schüpbach T;Shvartsman SY
通讯作者：
Shvartsman SY

Dynamics of Drosophila endoderm specification.