Nkx2-5 transcription in heart development

نویسندگان

  • Robert J. Schwartz
  • Eric N. Olson
چکیده

The heart is the first organ to form in mammals. Cardiogenic lineages originate from paired regions of anterior lateral mesoderm, the cardiac crescent, soon after gastrulation and develop into parallel cardiac primordia that fuse to form the primitive heart tube along the ventral midline of the embryo. Subsequent events of looping, chamber maturation and alignment with the vasculature give rise to the mature multichambered heart (Olson and Srivastava, 1996; Fishman and Chien, 1997). Based on the phenotypes of mouse and zebrafish mutants lacking cardiogenic regulatory genes, it has been proposed that the heart develops as a modular organ, such that each anatomical region is controlled by a distinct transcriptional regulatory program (Fishman and Olson, 1997). Consistent with this notion, the heart tube can be divided into segments that form the atria, left ventricle, right ventricle and ventricular outflow tract. Precursors of these regions of the heart appear to originate from separate lineages that develop according to their positions along the anteroposterior axis of the embryo (Yutzey and Bader, 1995). Several recent studies have revealed cis-regulatory elements that direct cardiac transcription specifically in the left or right ventricular chambers and atria, and even within subdomains within the chambers. Whether this regional specificity of transcription is important for the physiologic and functional differences of the chambers of the adult heart and how these transcriptional territories are established and maintained are issues of intense interest. The homeobox gene Nkx2-5 (also called Csx) (Lints et al., 1993; Komuro and Izumo, 1993) is the earliest known marker of vertebrate heart development and has been identified as a potential vertebrate homologue of tinman, a homeobox gene required for cardiac development in the Drosophila embryo (Azpiazu and Frasch, 1993; Bodmer, 1993; reviewed in Harvey, 1996). Deciphering the regulatory mechanisms that activate Nkx2-5 transcription in cardiac mesoderm is an important problem because it will provide a window into the cellular circuitry that specifies cardiac cell fate and may ultimately provide opportunities for cardiac regeneration. Recently, a series of papers has described cis-acting regulatory elements that control Nkx2-5 expression during heart development in the mouse. These studies have revealed surprising complexity in Nkx2-5 regulation, with multiple enhancers acting in distinct populations of cardiomyocytes during development. Here we describe a model for cardiac development based on the modularity of transcriptional units that control Nkx2-5 and suggest a potential role for this modularity in evolution of the multichambered heart.

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تاریخ انتشار 1999