Publication Date

2014-08-13

Availability

Embargoed

Embargo Period

2016-08-12

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Biology (Arts and Sciences)

Date of Defense

2014-07-02

First Committee Member

Isaac Skromne

Second Committee Member

Athula Wikramanayake

Third Committee Member

Julia Dallman

Fourth Committee Member

Pantelis Tsoulfas

Abstract

Understanding how the anatomical complexity of the nervous system arises is key to understanding the function of the nervous system. Neural development is a complex process consisting of multiple discrete steps regulated and coordinated by signaling events. Surprisingly, a rather small number of signals are implicated in regulating these vastly different neural developmental processes. A striking example is the case of the signaling molecule Fibroblast Growth Factor, or FGF, which regulates the induction of neural tissues from prospective ectoderm cells, regionalizes the neural tissue into forebrain, midbrain, hindbrain, and spinal cord, and provides discrete anterior-posterior (A-P) identity to hindbrain and spinal neurons in a manner that is ordered and patterned. This dissertation focuses on understanding the molecular switches that allow FGF to regionalize and then pattern the most posterior regions of the neural tissue, the hindbrain and spinal cord. Using the zebrafish as an experimental model system to increase or eliminate gene and signaling pathway activities, data presented here shows that the regionalization and patterning functions of FGF are regulated by the transcription factor Cdx4. Based on this evidence, a model is proposed in which feedback cooperation between Cdx4 and FGF signals are essential for the proper spatial and temporal regulation of a large family of A-P patterning genes, the hox family of transcription factors. In this way, emergence of the hindbrain and spinal cord regions and the subsequent A-P patterning is dependent on the sequential activation of different classes of transcription factors that can change the response of cells to those very same signals in a unidirectional way. This sequential and unidirectional activation of genes by signaling regulators may be a common mechanism to drive development during embryogenesis.

Keywords

Cdx; hox genes; FGF; neural specification; neural patterning

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