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Optogenetic dissection of Erk signal interpretation in early embryogenesis

早期胚胎发生中 Erk 信号解释的光遗传学解析

基本信息

批准号：
10679294
负责人：
Emily Kolenbrander Ho
金额：
$ 6.95万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679294
关键词：
Address Affect Anterior Biosensor Cancer Etiology Cells Cellular biology Complex Decision Making Development Developmental Biology Diffusion Disease Dissection Dose Drosophila genus Drosophila melanogaster Ectoderm Embryo Embryonic Development Endoderm Event Extracellular Signal Regulated Kinases Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Genomic approach Genomics Goals Growth Head Human Development Laboratories Light Malignant Neoplasms Measures Mediating Microscopy Midgut Molecular Mutation Output Pathway interactions Pattern Physiologic pulse Play Positioning Attribute Proteins Reporter Research Role Signal Pathway Signal Transduction Spatial Distribution Specific qualifier value Structure Tail Time Tissue Model Tissues Training Travel Work career gastrulation genetic manipulation imaging approach in vivo in vivo Model innovation optogenetics programs response tool transcription factor transcriptome sequencing tumor progression wound healing

项目摘要

PROJECT SUMMARY/ABSTRACT Signaling pathways pattern cell fate choices in the developing embryo, but how do only a limited number of pathways control the complex events of development? Spatial signaling gradients as well as temporal signaling dynamics are known to be important for directing multiple fates with the same pathway, yet the mechanisms cells use to interpret these signaling events remains largely uncharacterized. One pathway which plays diverse roles throughout embryogenesis, wound healing, and cancer progression is the highly conserved extracellular signal-regulated kinase (Erk) signaling network. The early Drosophila embryo is a classic in vivo model of tissue patterning by Erk signaling: a spatial gradient of Erk signal at the poles specifies anterior and posterior structure and dictates endoderm versus ectoderm fate decisions. Although these patterns are well-defined, recent work in the Toettcher laboratory using an optogenetic tool to manipulate the Erk signal in vivo with exquisite spatial and temporal precision has revealed major open questions about the mechanisms by which Erk signals are interpreted. Here, I propose to define the mechanisms by which the Drosophila embryo interprets differences in Erk dose to create spatial patterns of gene expression and make decisions about cell fate. To address this question, I will use a combination of cutting-edge optogenetic tools, live-cell biosensors, genomic analysis, and classical genetic perturbations. In Aim 1, I will examine how spatial patterns of gene expression are robust to major corruption of the Erk gradient. In Aim 2, I will explore how only two transcription factors can control multiple distinct fates over a wide range of Erk signal strength. Altogether, using precision tools for manipulating signaling inputs and quantifying expression outputs, this proposal will reveal how Erk signals are measured and interpreted by downstream genes, addressing a fundamental question in developmental biology which will surely have relevance for other signaling pathways and cellular contexts for Erk signaling. Through this research and the accompanying training plan I will obtain exceptional training in optogenetics, advanced microscopy, and genomics, positioning me for an impactful career at the interface of cell and developmental biology.

项目总结/文摘