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Title page for ETD etd-03202007-192359

Type of Document Dissertation
Author Ohi, Yuki
URN etd-03202007-192359
Title Long-range Nodal Signaling in Vertebrate Left-Right Specification
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Dr. Chris Wright Committee Member
  • L-R asymmetry
  • Xenopus laevis
  • lateral plate mesoderm
  • Xnr1
  • Nodal
  • Transforming growth factors-beta
  • Pattern formation (Biology)
Date of Defense 2006-12-20
Availability unrestricted
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 expression within the L LPM. Preliminarily, I found that Xnr1 and Xlefty transcripts are rapidly degraded upon inhibiting the Xnr1 autoregulatory loop, providing novel insight into the stability of these mRNAs.

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