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Quantitative Biology of Developmental Ras Signaling : = From Molecules to Morphologies.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Quantitative Biology of Developmental Ras Signaling :/
Reminder of title:	From Molecules to Morphologies.
Author:	Goyal, Yogesh.
Description:	1 online resource (88 pages)
Notes:	Source: Dissertation Abstracts International, Volume: 79-05(E), Section: B.
Subject:	Chemical engineering. -
Online resource:	click for full text (PQDT)
ISBN:	9780355480337

Quantitative Biology of Developmental Ras Signaling : = From Molecules to Morphologies.
Goyal, Yogesh.

Quantitative Biology of Developmental Ras Signaling :From Molecules to Morphologies. - 1 online resource (88 pages)

Source: Dissertation Abstracts International, Volume: 79-05(E), Section: B.

Thesis (Ph.D.)--Princeton University, 2017.

Includes bibliographical references

Precision, reproducibility, and robustness are hallmarks of patterning events in animal development. How are such desirable properties imparted to biological systems? Specifically, what features of inductive signals allow for normal gene expression and patterning? At the same time, certain perturbations can derail development leading to abnormal outcomes. Such perturbations are often a result of alterations in the chemical properties, and thus the normal function, of signaling pathways. Can we identify causal relationships between the nature of perturbations and the emergent abnormalities? In this thesis, we attempt to answer some of these fundamental questions for developmental events driven by the highly conserved Ras signaling network. We focus primarily on the early embryonic patterning in Drosophila melanogaster, an experimental system uniquely suited for quantitative and high-throughput analyses of developmental signaling.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2018

Mode of access: World Wide Web

ISBN: 9780355480337Subjects--Topical Terms:

555952
Chemical engineering.
Index Terms--Genre/Form:

554714
Electronic books.

Quantitative Biology of Developmental Ras Signaling : = From Molecules to Morphologies.
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500 $a Source: Dissertation Abstracts International, Volume: 79-05(E), Section: B.
500 $a Adviser: Stanislav Y. Shvartsman.
502 $a Thesis (Ph.D.)--Princeton University, 2017.
504 $a Includes bibliographical references
520 $a Precision, reproducibility, and robustness are hallmarks of patterning events in animal development. How are such desirable properties imparted to biological systems? Specifically, what features of inductive signals allow for normal gene expression and patterning? At the same time, certain perturbations can derail development leading to abnormal outcomes. Such perturbations are often a result of alterations in the chemical properties, and thus the normal function, of signaling pathways. Can we identify causal relationships between the nature of perturbations and the emergent abnormalities? In this thesis, we attempt to answer some of these fundamental questions for developmental events driven by the highly conserved Ras signaling network. We focus primarily on the early embryonic patterning in Drosophila melanogaster, an experimental system uniquely suited for quantitative and high-throughput analyses of developmental signaling.
520 $a In the first part of this thesis (Chapter 2), we developed an optogenetic system in Drosophila for activating the extracellular signal--regulated kinase (ERK), a Ras pathway readout which controls multiple cellular processes. This enabled us to systematically probe the differential contributions of dose, duration and spatial range of ERK activity on development. Remarkably, we found that embryogenesis is robust to ectopic ERK activation, except from 1-4 h post-fertilization, when perturbing the spatial extent of ERK activation leads to dramatic disruptions of patterning and morphogenesis. The second part of the thesis (Chapters 3, 4, and 5) was motivated by a growing number of studies reporting that germline mutations in components of the Ras pathway give rise to developmental abnormalities, collectively known as RASopathies. Studies in cultured cells have demonstrated that these abnormalities may be caused by altered levels of Ras signaling, but the nature of changes in developing tissues remains largely unknown. We focused on pathogenic mutations in MEK, a core Ras pathway component, and quantified spatiotemporal changes in ERK activity caused by these mutations in fixed Drosophila embryos. Surprisingly, we discovered that intrinsically active MEK variants can both increase and reduce the levels of active ERK. The sign of the effect depends on cellular context, implying that some of the resulting phenotypes in RASopathies may be caused by increased, as well as attenuated, levels of Ras signaling. Going beyond the analysis of fixed embryos, we describe a parallel live imaging approach that can significantly increase the quantitative resolution of the ongoing functional studies of Ras pathway mutations. Our findings have broad implications for the basic understanding of a large class of genetic developmental abnormalities and present rational guidelines for thinking about their origins and potential treatment.
520 $a Together, my thesis combines genetic engineering, imaging, biochemistry, microfluidics, sequencing, and mathematical modeling to study developmental signaling at multiple levels of biological organization, from molecules to morphogenesis. Our work provides quantitative foundations for using multiscale approaches to uncover the general design and control principles governing natural systems.
533 $a Electronic reproduction. $b Ann Arbor, Mich. : $c ProQuest, $d 2018
538 $a Mode of access: World Wide Web
650 4 $a Chemical engineering. $3 555952
650 4 $a Developmental biology. $3 669036
650 4 $a Genetics. $3 578972
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710 2 $a Princeton University. $b Chemical and Biological Engineering. $3 845568
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