Publication Date

2016-07-27

Availability

Embargoed

Embargo Period

2018-07-27

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Biology (Arts and Sciences)

Date of Defense

2016-03-28

First Committee Member

Isaac Skromne

Second Committee Member

Athula H. Wikramanayake

Third Committee Member

Claudia D. O. Rodrigues

Fourth Committee Member

James D. Baker

Abstract

Cdx4 is a ParaHox family of transcription factor that regulates Hox gene function in patterning and imparts identity to different segments of the body of a vertebrate organism. Somitogenesis, is the periodic and sequential division of the paraxial mesoderm of a vertebrate organism into repetitive segments called somites, which are the precursors of the muscle, dermis and vertebrae. Somite formation is an outcome of strictly orchestrated programs that bring together aspects of growth, fate specification, movement and differentiation of the trunk-tail paraxial mesodermal tissue. Although extensive studies have been carried out to understand the function of Cdx4 in patterning, its contribution towards the process of segmentation and cell movement during somitogenesis is underexplored. Cdx4 deficient embryos have a reduced axis length and smaller posterior somites, indicating that any of the processes of segmentation, cell movement, progenitor cell maintenance or their cell fate specification could be compromised. This study is aimed at understanding the function of Cdx4 during somitogenesis. This research also addresses how Cdx4 interacts with morphogen gradient components to coordinate mesoderm segmentation to its patterning program. To address whether Cdx4 affects cell fate specification, expression of markers of paraxial mesodermal fate like the T-box family of transcription factors, Tbx6, Ntl, Tbx16, were studied and found to be unaffected in the absence of Cdx4. Tissue growth was mostly normal till mid segmentation stages. Periodicity of sequential somite formation was also unperturbed in the absence of Cdx4. However, the competency of cells to respond to periodic signals was impaired. Cdx4 was found to be an integral component of the signaling machinery that regulated the maturation state of cells undergoing segmentation. Additionally, this research demonstrated for the first time that Cdx4 coordinates the processes of segmentation and patterning during somitogenesis. It was also discovered that absence of Cdx4 leads to cell morphometric changes, reminiscent of changes observed in “convergence and extension” cell movement defective embryos. Lastly, this research also explored the role of Cdx4 in regulating the patterning program in the notochord. Loss of Cdx4 activity caused post anal notochord specification and patterning defects that might be responsible for added mechanical stress and axis curvature. While this research added novel functional relevance to Cdx4 activity during paraxial mesoderm segmentation, I believe future research would unravel newer aspects of Cdx4’s importance in embryo morphogenesis.

Keywords

Cdx4; Somitogenesis; Clock and wavefront; Axial patterning; Cell movement; Notochord

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