Abstract
BackgroundAdult stem cells play an essential role in adult organ physiology and tissue repair and regeneration. While much has been learnt about the property and function of various adult stem cells, the mechanisms of their development remain poorly understood in mammals. Earlier studies suggest that the formation of adult mouse intestinal stem cells takes place during the first few weeks after birth, the postembryonic period when plasma thyroid hormone (T3) levels are high. Furthermore, deficiency in T3 signaling leads to defects in adult mouse intestine, including reduced cell proliferation in the intestinal crypts, where stem cells reside. Our earlier studies have shown that protein arginine methyltransferase 1 (PRMT1), a T3 receptor coactivator, is highly expressed during intestinal maturation in mouse.MethodsWe have analyzed the expression of PRMT1 by immunohistochemistry and studied the effect of tissue-specific knockout of PRMT1 in the intestinal epithelium.ResultsWe show that PRMT1 is expressed highly in the proliferating transit amplifying cells and crypt base stem cells. By using a conditional knockout mouse line, we have demonstrated that the expression of PRMT1 in the intestinal epithelium is critical for the development of the adult mouse intestine. Specific removal of PRMT1 in the intestinal epithelium results in, surprisingly, more elongated adult intestinal crypts with increased cell proliferation. In addition, epithelial cell migration along the crypt-villus axis and cell death on the villus are also increased. Furthermore, there are increased Goblet cells and reduced Paneth cells in the crypt while the number of crypt base stem cells remains unchanged.ConclusionsOur finding that PRMT1 knockout increases cell proliferation is surprising considering the role of PRMT1 in T3-signaling and the importance of T3 for intestinal development, and suggests that PRMT1 likely regulates pathways in addition to T3-signaling to affect intestinal development and/or homeostasis, thus affecting cell proliferating and epithelial turn over in the adult.
Highlights
Adult vertebrate organs/tissues that are exposed to the external environment, such as skin and hair, undergo self-renewal to maintain tissue homeostasis and repair damages due to the external exposure
Our results suggest that protein arginine methyltransferase 1 (PRMT1) plays a critical role in the maturation of the intestine and/or maintenance of the adult intestine, likely through a function other than as a T3 receptor (TR) coactivator
Intestinal epithelium‐specific knockout of PRMT1 leads to altered adult intestinal structure To overcome the embryonic lethal phenotype due to total PRMT1 knockout, we obtained a PRMT1 mouse line (PRMT1LoxP) from Wellcome Trust Sanger Institute
Summary
Adult vertebrate organs/tissues that are exposed to the external environment, such as skin and hair, undergo self-renewal to maintain tissue homeostasis and repair damages due to the external exposure. Throughout adult life, the intestinal epithelium is replaced once every 1–6 days in mammals [1,2,3] This occurs through the proliferation of the adult intestinal stem cells localized in the crypt. As the cells migrate along the crypt-villus axis, they differentiate into various types of epithelial cells and the fully differentiated epithelial cells are removed through apoptosis, mostly near the tip of the intestinal villus Such a rapid and compete self-renewing process has led to extensive studies on the function and properties of the adult intestinal stem cells, with many genes and signaling pathways critical for the adult stem cells discovered and characterized over the years [3, 4]. Our earlier studies have shown that protein arginine methyltransferase 1 (PRMT1), a T3 receptor coactivator, is highly expressed during intestinal matura‐ tion in mouse
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