Abstract
Bmi-1 prevents stem cell aging, at least partly, by blocking expression of the cyclin-dependent kinase inhibitor p16Ink4a. Therefore, dysregulation of the Bmi-1/p16Ink4a pathway is considered key to the loss of tissue homeostasis and development of associated degenerative diseases during aging. However, because Bmi-1 knockout (KO) mice die within 20 weeks after birth, it is difficult to determine exactly where and when dysregulation of the Bmi-1/p16Ink4a pathway occurs during aging in vivo. Using real-time in vivo imaging of p16Ink4a expression in Bmi-1-KO mice, we uncovered a novel function of the Bmi-1/p16Ink4a pathway in controlling homeostasis of the submandibular glands (SMGs), which secrete saliva into the oral cavity. This pathway is dysregulated during aging in vivo, leading to induction of p16Ink4a expression and subsequent declined SMG function. These findings will advance our understanding of the molecular mechanisms underlying the aging-related decline of SMG function and associated salivary gland hypofunction, which is particularly problematic among the elderly.
Highlights
In higher eukaryotes, maintenance of adult stem and progenitor cells is indispensable for tissue homeostasis throughout the lifespan of the organism (Cheung & Rando, 2013)
Because Bmi-1-KO mice die within 20 weeks after birth, it is difficult to determine exactly where and when dysregulation of the Bmi-1/p16Ink4a pathway occurs during aging in vivo
Our findings showed that the Bmi-1/p16Ink4a pathway becomes dysregulated in submandibular glands (SMGs) during the aging process, which leads to induction of p16Ink4a expression and the subsequent decline of SMG function
Summary
Maintenance of adult stem and progenitor cells is indispensable for tissue homeostasis throughout the lifespan of the organism (Cheung & Rando, 2013). Regulation of these processes declines with age, resulting in an increased incidence of various aging-associated degenerative diseases (Sharpless & DePinho, 2007; Liu & Rando, 2011; Behrens et al, 2014). Better understanding of the downstream mediators of the Bmi-1 pathway will likely facilitate the development of new strategies for prevention or intervention of aging-associated degenerative diseases
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