Petchey, LK; (2013) Investigating the role of Prox1 in cardiac and skeletal muscle development and disease. Doctoral thesis , UCL (University College London).

Abstract

Restricted expression of contractile protein gene isoforms contributes to the functional distinction between cardiac and skeletal striated muscle types, with these genes often misregulated in myopathic disease. The homeobox transcription factor Prox1 is expressed in both cardiac and skeletal muscle, and ablation of Prox1 specifically within cardiomyocytes resulted in the abnormal upregulation of the fast-twitch skeletal isoforms of the contractile protein genes troponin T (Tnnt3), troponin I (Tnni2), and MyLC 1 (Myl1) from early in heart development. Similar loss of function studies in skeletal muscle using a Myf5-driven Cre revealed overexpression of these same fast-twitch genes specifically in slow-twitch skeletal muscle, identifying Prox1 as the first transcription factor known to directly repress a program of fast-twitch skeletal genes across both cardiac and skeletal striated muscle types. Furthermore, loss of Prox1 expression in skeletal muscle was sufficient to cause a switch from a slow to a fast-twitch fibre-type, which has not previously been reported following knockout of a single transcription factor. Intriguingly, aberrant expression of Tnnt3, Tnni2, and Myl1 has been observed in other muscle-specific knockout models, including HDAC1/2 and miR-208a (cardiac), and Sox6 and miR-208b/miR-499 (skeletal), where the transcription factor directly responsible for their misexpression remains to be demonstrated. Recent work has revealed a lack of conservation in the regulation of these genes from the zebrafish, suggesting that in the mouse this role may be fulfilled by Prox1. This study has additionally uncovered novel putative regulatory relationships between Prox1 and miRNAs implicated in cardiac and/or skeletal muscle development, function, or disease, using a high-throughput in vitro screen. Herein is also the first description of the heart phenotype of survived cardiac-specific Prox1 knockouts, which develop severe dilated cardiomyopathy that is fatal within the first 14 weeks of life. Consequently, these mice model the functional impact of loss of Prox1 function on the adult heart, including the effect of ectopic fast-twitch contractile protein gene expression, and the molecular pathways that underlie the development of dilated cardiomyopathy. An improved understanding of the function of Prox1 in the developing and adult heart may provide new opportunities for therapeutic intervention.

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