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Title page for ETD etd-11302008-131316


Type of Document Dissertation
Author Chopra, Sameer
Author's Email Address sameer.chopra@vanderbilt.edu
URN etd-11302008-131316
Title Sodium channels are required for cardiac cell-fate specification via a novel, non-electrogenic mechanism in zebrafish.
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Al George Committee Chair
Bruce Appel Committee Member
Dan Roden Committee Member
Joey Barnett Committee Member
Ron Emeson Committee Member
Tao Zhong Committee Member
Keywords
  • heart
  • cardiac development
  • cardiomyopathy
  • zebrafish
  • Sodium channels
  • electrophysiology
  • animal models of disease
  • arrhythmia
  • Zebra danio -- Development
  • Heart -- Differentiation
Date of Defense 2007-08-10
Availability unrestricted
Abstract
Electrical signaling events are required for each human thought, feeling, and perception, the movement of our limbs, and the beat of our hearts. As the initiators of action potentials in excitable tissues, voltage-gated sodium channels play significant roles in both normal and pathological signaling events. In the heart, the opening of sodium channels initiates the cardiac cycle and mutations in the gene encoding the cardiac sodium channel are linked to heritable arrhythmias. Here we define a previously-unappreciated role for sodium channels in heart development. In zebrafish, knockdown of cardiac sodium channel expression in early embryos resulted in a failure of chamber morphogenesis and looping. We found these abnormalities to be associated with a significant deficit in the production of cardiac progenitor cells due to the perturbed expression of key transcription factors in early cardiac primordia. Pharmacological blockade of sodium channels did not recapitulate the effects of channel knockdown. These results suggest that voltage-gated sodium channels have evolved two distinct roles in the vertebrate heart: in addition to acting as the principal orchestrators of heart rhythm, they perform a previously-unappreciated, non-electrogenic function in early cardiogenesis. This dissertation describes the identification, cloning, and characterization of zebrafish cardiac sodium channel á and â subunits in early heart development and function.
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