Tim Mohun

Heart Development Laboratory

The Mohun lab is interested in how the vertebrate heart develops during embryogenesis. Formation of the heart is a complex process that begins very early in the vertebrate embryo, remodelling a simple pulsatile tube into a multi-chambered organ capable of supporting embryo growth.

This transformation requires exquisite coordination of cell differentiation, growth and dramatic changes in organ shape. Abnormalities affecting any step have profound consequences on the foetal heart, with the result that heart defects are the most common birth defect.

By studying the roles of individual genes and cell populations in normal heart development, our work aims to provide a better understanding of the origins of cardiac malformations and how this complex organ is formed in the developing embryo. This may also contribute to our understanding of cardiac disease since accumulating evidence suggests that the same genes regulating normal heart development are important in both the normal and pathological adult heart phenotype.

Figure

The Xenopus myosin light chain 2 promoter drives expression in the heart of tadpoles (A) and transgenic mice (B).

Since many of the basic steps in heart formation are similar in all vertebrates, valuable information can be obtained from studying a variety of different species. We are using transgenic and genomic methods to examine how gene expression is regulated in the developing heart of vertebrate embryos (primarily frog and mouse) and to assess their possible contribution to adult heart disease.

Genome-wide chromatin immunoprecipitation methods and targeted gene manipulation are being used to study transcriptional regulation during heart development and to investigate transformations in heart structure and energetics at birth. 3D imaging and computer modelling procedures are being developed in parallel to provide systematic and quantitative ways to monitor effects of normal and altered gene expression on heart morphology and to identify novel roles of genes in cardiac morphogenesis.

Xenopus Transgenic reporter lines

Xenopus Transgenic reporter lines. (A & B) Nkx2-5:GFP, St30 and St46 heart region; (C) MLC2:GFP, St30 (Click to view larger image)

Current projects

  • High Resolution Episcopic Microscopy (HREM)

  • DMDD (Deciphering the Mechanisms of Developmental Disorders)

  • Nkx2-5 transcriptional targets

  • Down syndrome cardiac defects

  • Ventricular compaction and disease

  • HAND1 in heart homeostasis

     

Selected publications

Dunlevy, L; Bennett, M; Slender, A; Lana-Elola, E; Tybulewicz, VL; Fisher, EMC and Mohun, T (2010) Down syndrome-like cardiac developmental defects in embryos of the transchromosomic Tc1 mouse. Cardiovascular Research 88, 287-295

Breckenridge, RA; Zuberi, Z; Gomes, J; Orford, R; Dupays, L; Felkin, LE; Clark, JE; Magee, AI; Ehler, E; Birks, EJ; Barton, PJ; Tinker, A and Mohun, TJ (2009) Overexpression of the transcription factor Hand1 causes predisposition towards arrhythmia in mice. Journal of Molecular and Cellular Cardiology 47, 133-141

Dupays L, Kotecha S, Angst B, Mohun TJ. (2009) Tbx2 misexpression impairs deployment of second heart field derived progenitor cells to the arterial pole of the embryonic heart. Developmental Biology 333, 121-131

Weninger, WJ and Mohun, TJ (2007) Three-dimensional analysis of molecular signals with episcopic imaging techniques. Methods in Molecular Biology 411, 35-46

Breckenridge R, Kotecha S, Towers N, Bennett M, Mohun T. (2007) Pan-myocardial expression of Cre recombinase throughout mouse development. Genesis 45, 135-44