Generation of distinct atrial and ventricular cell lineages in the heart is essential for cardiovascular function and plays a critical role in the formation of heart chambers by determining the placement of valves and septa. The long term goal of this research is to understand the molecular interactions governing heart pattern formation and organogenesis. The purpose of the proposed experiments is to isolate and characterize Hox genes expressed in the developing heart and to determine whether they are involved in establishing positional information within the cardiogenic mesoderm thereby effecting atrial vs. ventricular cell lineage determination events. The hypothesis is that differential expression of Hox genes along the anteroposterior axis of the developing heart is involved in the specification and patterning of cardiomyogenic lineages. A preliminary screen for Hox genes expressed in the developing chicken heart revealed that among the most abundant proteins of this class present during the early stages of heart formation are hoxa-4, hoxd-3 and hoxd-4.
The aims of the proposed research include 1) Isolation and sequence analysis of Hox genes expressed during the early heart formation; 2) Determination of Hox gene expression platterns surroundign the border between atrial and ventricular cardiomyogenic lineages; and 3) Alteration of Hox gene expression patterns that characterize the atrial/ventricular border of the heart forming region. Using the chicken embryo as an experimental system, targeted genetic alterations in Hox gene expression will be made both in whole embryos and in cardiogenic cells in culture with retroviral expression vectors and antisense oligonucleotides. It is argued that the analysis of Hox expression during cardiomyogenesis and the assessment of the effects of Hox gain or loss of function on atrial vs. ventricular lineage specification will provide direct evidence of genetic regulation of cardiomyogenesis and pattern formation by Hox expression. These analyses will provide mechanistic data on the molecular basis of cardiac lineage diversification.
| Ehrman, L A; Yutzey, K E (2001) Anterior expression of the caudal homologue cCdx-B activates a posterior genetic program in avian embryos. Dev Dyn 221:412-21 |
| Liberatore, C M; Searcy-Schrick, R D; Yutzey, K E (2000) Ventricular expression of tbx5 inhibits normal heart chamber development. Dev Biol 223:169-80 |
| Ehrman, L A; Yutzey, K E (1999) Lack of regulation in the heart forming region of avian embryos. Dev Biol 207:163-75 |
| Searcy, R D; Yutzey, K E (1998) Analysis of Hox gene expression during early avian heart development. Dev Dyn 213:82-91 |
