Abstract
BackgroundSmooth muscle cell (SMC) plasticity maintains the balance between differentiated SMCs and proliferative mesenchymal progenitors, crucial for muscular tissue homeostasis. Studies on the development of mesenchymal progenitors into SMCs have proven useful in identifying molecular mechanisms involved in digestive musculature plasticity in physiological and pathological conditions.ResultsHere, we show that Limb Expression 1 (LIX1) molecularly defines the population of mesenchymal progenitors in the developing stomach. Using in vivo functional approaches in the chick embryo, we demonstrate that LIX1 is a key regulator of stomach SMC development. We show that LIX1 is required for stomach SMC determination to regulate the expression of the pro-proliferative gene YAP1 and mesenchymal cell proliferation. However, as stomach development proceeds, sustained LIX1 expression has a negative impact on further SMC differentiation and this is associated with a decrease in YAP1 activity.ConclusionsWe demonstrate that expression of LIX1 must be tightly regulated to allow fine-tuning of the transcript levels and state of activation of the pro-proliferative transcriptional coactivator YAP1 to regulate proliferation rates of stomach mesenchymal progenitors and their differentiation. Our data highlight dual roles for LIX1 and YAP1 and provide new insights into the regulation of cell density-dependent proliferation, which is essential for the development and homeostasis of organs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0257-2) contains supplementary material, which is available to authorized users.
Highlights
Smooth muscle cell (SMC) plasticity maintains the balance between differentiated smooth muscle cells (SMCs) and proliferative mesenchymal progenitors, crucial for muscular tissue homeostasis
While high levels of Limb Expression 1 (LIX1) transcripts were detected at embryonic day 4 (E4), levels of LIX1 transcripts quickly decreased with the onset of SMC determination, to barely detectable levels at E7, when SMC differentiation occurred
We monitored the levels of BARX1, a marker of stomach mesenchyme [19], as well as SRF and its co-activator MYOCARDIN, which control SMC differentiation [20, 21], and found that, while the onset of MYOCARDIN expression occurs at E5.5, the stage of SMC determination, SRF and BARX1 were detected throughout all examined stages
Summary
Smooth muscle cell (SMC) plasticity maintains the balance between differentiated SMCs and proliferative mesenchymal progenitors, crucial for muscular tissue homeostasis. Studies on the development of mesenchymal progenitors into SMCs have proven useful in identifying molecular mechanisms involved in digestive musculature plasticity in physiological and pathological conditions. The mesoderm gives rise to the digestive mesenchyme, which in turn differentiates into multiple tissues, such as the submucosa and the musculature, which is composed of smooth muscle cells (SMCs) and interstitial cells of Cajal [1, 2]. SMCs have the unique ability to switch between a differentiated, quiescent contractile state and a highly proliferative and migratory phenotype in response to internal or external cues [1, 4]. SMC plasticity plays crucial roles in maintaining muscular tissue homeostasis during perinatal development and postnatal
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