mCAT got youR TEF?

TEF and RTEF-1 Binding to the Smooth Muscle -Actin Gene Distinguishes Myofibroblasts and Adult Smooth Muscle Cells Adult smooth muscle cells are highly plastic and can exhibit a range of phenotypes in response to different environmental and developmental cues. Their phenotypes can range from quiescent highly contractile cells with high levels of characteristic contractile protein isoforms, to highly proliferative cells that secrete large amounts of extracellular matrix and express only low levels of smooth muscle-specific isoforms of contractile proteins. These two states are often referred to as differentiated and dedifferentiated or phenotypically modulated states.1 In reality the situation is more complex, with smooth muscle cells likely existing in a continuum of phenotypes between these two extremes. This smooth muscle cell plasticity often makes the unequivocal identification of smooth muscle cells challenging, particularly for the more dedifferentiated smooth muscle cells that are very similar to fibroblasts. The situation is further complicated by the existence of cell types with phenotypes part way between a fibroblast and a fully differentiated adult smooth muscle cell, namely myoepithelial and myofibroblast cells, and pericytes.2–4 A major challenge to developmental biologists is determining how these cells relate to each other, determining whether they are derived from common or distinct precursors, and whether myofibroblasts or pericytes can become smooth muscle cells. One approach to begin to answer these questions is to determine the molecular mechanisms that control the phenotype of each of these cell types. A new study by Gan and colleagues,5 described in this issue of Circulation Research, provides definitive molecular evidence that distinguishes myofibroblasts from adult smooth muscle cells by the distinct transcriptional mechanisms that they use to direct expression of a shared molecular marker, smooth muscle -actin. In this elegant study, the authors demonstrate that the binding of RTEF-1 to MCAT elements within the smooth muscle -actin promoter is required for transcription in myofibroblasts but not in adult smooth muscle cells (Figure). These results reveal that although both adult smooth muscle cells and myofibroblasts express smooth muscle -actin, its expression in these cell types is regulated by distinct cisand trans-acting factors. That myofibroblasts and adult smooth muscle cells use distinct cis-regulatory elements to control expression of a single gene should not, however, be too surprising given previous studies showing that a single gene often uses distinct elements for expression even among adult smooth muscle cells in different tissues. This phenomenon is perhaps best illustrated by earlier studies by the Owens group which showed that distinct regions of the smooth muscle myosin heavy chain gene direct expression in different vascular beds and among different visceral smooth muscle tissues.6 Perhaps the most intriguing finding of this study is that the MCAT elements required for expression of smooth muscle -actin in myofibroblasts are also required for expression in smooth muscle cells during early embryonic development. This provides unequivocal evidence that smooth muscle cells also use distinct regulatory elements to drive expression of a gene in embryonic and adult cells. This finding certainly begs the question as to what distinguishes an embryonic smooth muscle cell from a myofibroblast and raises the possibility that myofibroblasts could represent a resident population of embryonic smooth muscle cells that persist, undifferentiated, in an adult. Careful lineage mapping using temporally and spatially restricted lineage markers will be required to answer this important question.