Publication Date

2017-04-30

Availability

Embargoed

Embargo Period

2019-04-30

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Biology (Arts and Sciences)

Date of Defense

2017-04-06

First Committee Member

Isaac Skromne

Second Committee Member

Donald L. DeAngelis

Third Committee Member

Julia Dallman

Fourth Committee Member

Pantelis Tsoulfas

Abstract

Deciphering the mechanisms involved in regulating cell fate decisions is crucial to understanding the development of living organisms. Cells transition from one cellular state to another during the process of differentiation, ultimately acquiring specialized functions. At each step in the differentiation pathway the next state is prescribed by the regulatory state of the cell, as defined by the totality of the active transcription factors. The activity of these transcription factors determines the response of the cell to the signaling information it may encounter in its immediate surroundings, thus dictating the path taken by the cell in response to the environmental cues. Signaling information in turn regulates the activity of transcription factors that drives differentiation. This cross-regulation between transcription and signaling factors results into a complex network that coordinates developmental events. Hence in order to understand development, it is important to decipher the specific role signaling and transcription factors play in driving differentiation. The differentiation of neuromesodermal progenitors into neuronal cells provides a striking example of sequential fate transition cued by signals. At the caudal end of the embryo, FGF/Wnt signals antagonize retinoic acid signal to regulate the sequential spatio-temporal maturation of spinal cord cells, from their exit out of the caudal neural progenitor stem zone to their incorporation into the developing neural tube. How the downstream transcription network, that is active in the cells, responds to the overlying signaling dynamics is not fully understood. In this dissertation I focused on deciphering the transcription network that interprets the FGF/Wnt and retinoic acid gradient information leading to progressive cell maturation states. Using transient gene manipulation techniques in chicken embryos, this work supports the role of Cdx4 as a core transcription factor that integrate upstream FGF, Wnt and retinoic acid signaling information to regulate the sequential maturation of cells from a biopotent neuromesodermal identity to a neurogenic identity. Based on experimental data, this work proposes a network of gene interactions that regulates the progressive maturation of neuromesodermal progenitors into differentiated spinal cord neural progenitors. Using computational and mathematical simulation of the gene regulatory network, the second part of this work highlights the core function Cdx4 plays in regulating the spatio-temporal pace of maturation events. The study provides evidences for Cdx as a core integrator of signaling information regulating cell fate decision in the embryonic caudal neural tube.

Keywords

Cdx4; Spinal cord, Neurogenesis; differentiation; gene regulatory network

Available for download on Tuesday, April 30, 2019

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