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Principal Investigator: Emily Kolenbrander Ho
Organization: PRINCETON UNIVERSITY
Fiscal Year: 2024
Award: $76,756
Funding agency: National Institute of General Medical Sciences
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.
Terms: <Address><Affect><Anterior><Basal Transcription Factor><Basal transcription factor genes><Biosensor><Body Tissues><Cancer Cause><Cancer Etiology><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular biology><Complex><Decision Making><Development><Developmental Biology><Diffusion><Disease><Disorder><Dissection><Dose><Drosophila><Drosophila genus><Drosophila melanogaster><ERK MAP Kinases><Ectoderm><Embryo><Embryo Development><Embryogenesis><Embryonic><Embryonic Development><Endoderm><Event><Expression Signature><Extracellular Signal Regulated Kinases><Extracellular Signal-Regulated MAP Kinases><Gene Expression><Gene Expression Profile><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genomic approach><Genomics><Goals><Growth><Head><Human Development><Intracellular Communication and Signaling><Laboratories><Light><MAPK ERK Kinases><Malignant Neoplasms><Malignant Tumor><Measures><Mediating><Microscopy><Midgut><Molecular><Mutation><Output><Pathway interactions><Pattern><Photoradiation><Physiologic pulse><Play><Position><Positioning Attribute><Proteins><Pulse><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Reporter><Research><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Spatial Distribution><Specific qualifier value><Specified><Structure><Tail><Threonine/Tyrosine Protein Kinase><Time><Tissue Growth><Tissue Model><Tissues><Training><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Travel><Work><Wound Repair><biological sensor><biological signal transduction><cancer progression><career><cell biology><developmental><diffused><diffuses><diffusing><diffusions><extracellular signal related kinase><fruit fly><gastrulation><gene expression pattern><gene expression signature><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><genome mutation><genomic effort><genomic strategy><imaging approach><imaging based approach><in vivo><in vivo Model><innovate><innovation><innovative><malignancy><neoplasm progression><neoplasm/cancer><neoplastic progression><ontogeny><optogenetics><pathway><programs><response><social role><tool><transcription factor><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><tumor progression><wound healing><wound recovery><wound resolution>