Long-range Nodal Signaling in Vertebrate Left-Right Specification.
Degree: PhD, Cell and Developmental Biology, 2007, Vanderbilt University
Transient asymmetric Nodal signaling in the left lateral plate mesoderm (L LPM) during tailbud/early somitogenesis stages is associated in all vertebrates examined with the development of stereotypical left-right (L-R) organ asymmetry. In Xenopus, asymmetric expression of Nodal-related 1 (Xnr1) begins in the posterior L LPM shortly after the initiation of bilateral perinotochordal expression in the posterior tailbud. The L LPM expression domain rapidly shifts forward to cover much of the flank of the embryo before being progressively downregulated, also in a posterior-to-anterior (P-to-A) direction. The mechanisms underlying the initiation and propagation of Nodal/Xnr1 expression in the L LPM, and its transient nature, are not well understood. Removing the posterior tailbud domain prevents Xnr1 expression in the L LPM, consistent with the idea that normal embryos respond to a posteriorly derived asymmetrically acting positive inductive signal. The forward propagation of asymmetric Xnr1 expression occurs LPM-autonomously via planar tissue communication. The shifting is prevented by Nodal signaling inhibitors, implicating an underlying requirement for Xnr1-to-Xnr1 induction.
It is also unclear how asymmetric Nodal signals are modulated during L-R patterning. Small LPM grafts overexpressing Xnr1 placed into the R LPM of tailbud embryos induced the expression of the normally L-sided genes Xnr1, Xlefty, and XPitx2, and inverted body situs, demonstrating the late-stage plasticity of the LPM. Orthogonal Xnr1 signaling from the LPM strongly induced Xlefty expression in the midline, consistent with findings in the mouse and demonstrating for the first time in another species conservation in the mechanism that induces and maintains midline barrier function. My studies suggest that there is long range contralateral communication between L and R LPM, involving Xlefty in the midline, over a substantial period of tailbud embryogenesis, and therefore lend further insight into how, and for how long, the midline maintains a L versus R status in the LPM. My results directly support very recent findings in mouse that were gathered concurrently and that led to a SELI (Self-Enhancement and Lateral Inhibition) model for pan-embryonic integration of L-R asymmetry information by communication across the midline. The consistency in findings between mouse and Xenopus demonstrate further conservation in the L-R specification program.
The unidirectional P-to-A shifting of Xnr1 expression in the L LPM during tailbud stages occurs rapidly within ~6-8 hours. It is uncertain whether the time that is required for the biochemical processes involved in signal receipt, intracellular signal transduction, ligand production and secretion between individual cells can occur fast enough to be accommodated during the period of observed Xnr1 expression shifting. I used a pharmacological approach to block Xnr1 signaling specifically at the level of the receptor to further investigate the role of Xnr1 autoregulation in maintaining and propagating its own…
Advisors/Committee Members: Dr. Chris Wright (committee member).
Subjects/Keywords: L-R asymmetry; Xenopus laevis; lateral plate mesoderm; Xnr1; Nodal; Transforming growth factors-beta; Pattern formation (Biology)
to Zotero / EndNote / Reference
APA (6th Edition):
Ohi, Y. (2007). Long-range Nodal Signaling in Vertebrate Left-Right Specification. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://etd.library.vanderbilt.edu/available/etd-03202007-192359/ ;
Chicago Manual of Style (16th Edition):
Ohi, Yuki. “Long-range Nodal Signaling in Vertebrate Left-Right Specification.” 2007. Doctoral Dissertation, Vanderbilt University. Accessed February 28, 2020.
MLA Handbook (7th Edition):
Ohi, Yuki. “Long-range Nodal Signaling in Vertebrate Left-Right Specification.” 2007. Web. 28 Feb 2020.
Ohi Y. Long-range Nodal Signaling in Vertebrate Left-Right Specification. [Internet] [Doctoral dissertation]. Vanderbilt University; 2007. [cited 2020 Feb 28].
Available from: http://etd.library.vanderbilt.edu/available/etd-03202007-192359/ ;.
Council of Science Editors:
Ohi Y. Long-range Nodal Signaling in Vertebrate Left-Right Specification. [Doctoral Dissertation]. Vanderbilt University; 2007. Available from: http://etd.library.vanderbilt.edu/available/etd-03202007-192359/ ;