DOI

https://doi.org/10.25772/2DG7-KR38

Defense Date

2010

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Life Sciences

First Advisor

Robert Tombes

Abstract

Ca2+/calmodulin-dependent protein kinase type II (CaMK-II) is a multifunctional serine/threonine kinase that is ubiquitously expressed throughout the lifespan of metazoans. Mammals encode four genes (α, β, γ, δ) that generate over forty splice-variants. CaMK-II is important in a myriad of functions, including ion channel regulation, cell-cycle progression, and long term potentiation. In adults, alterations in activation of CaMK-II induce cardiac arrhythmias and heart failure. Developmental roles for CaMK-II are not as well understood since mouse knockouts are embryonic lethal. Therefore the identification of other vertebrate CaMK-II genes will add to our understanding of development. Zebrafish encode seven catalytically active CaMK-II genes (α1, β1, β2, γ1, γ2, δ1, δ2) due to a genome wide duplication event that occurred approximately 250 million years ago. Although, only 20-30% of all duplicated genes were retained, 75% of CaMK-II duplicated genes are transcriptionally active, pointing to a critical role for this signaling protein. mRNA expression patterns demonstrate that CaMK-II is expressed in diverse tissues including retina, pectoral fins, somites, heart, and kidney. Suppression of each gene generates unique phenotypes that mirror the mRNA expression patterns. Of the seven genes, camk2b2 and camk2g1 have the highest maternal contribution in zebrafish, are expressed in mesodermally derived organs, and develop defects similar to human syndromes. In fact, suppression of camk2b2 mimics the phenotype observed in zebrafish mutants of tbx5, the gene mutated in patients with Holt-Oram Syndrome. Camk2g1 morphants also exhibit similar defects as suppression of pkd2, the gene mutated in patients with Autosomal Dominant Polycystic Kidney disease. These roles implicate CaMK-II as an integral protein in the development and maintenance of mesodermally derived tissues.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-12-2010

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