HYPOTHESIS: Do LRIG Proteins Regulate Stem Cell Quiescence by Promoting BMP Signaling?

Abstract

Leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins are evolutionarily conserved integral membrane proteins. Mammalian LRIG1 regulates stem cell quiescence in various tissue compartments, including compartments in the epidermis, oral mucosa, intestines, neural system, and incisors. The planarian LRIG1 homolog regulates the quiescence of multipotent neoblasts. The mechanism through which LRIG proteins regulate stem cell quiescence has not been well documented, although it is generally assumed that LRIG1 regulates the epidermal growth factor receptor (EGFR) or other receptor tyrosine kinases. However, Lrig-null (Lrig1-/-;Lrig2-/-; and Lrig3-/-) mouse embryonic fibroblasts (MEFs) have been recently found to exhibit apparently normal receptor tyrosine kinase functions. Moreover, bone morphogenetic protein (BMP) signaling has been shown to depend on LRIG1 and LRIG3 expression. BMPs are well-known regulators of stem cell quiescence. Here, we hypothesize that LRIG1 might regulate stem cell quiescence by promoting BMP signaling. HYPOTHESIS: Based on recent findings, it is hypothesized that LRIG1 regulates stem cell quiescence in mammalian tissues as well as in planarian neoblasts by promoting BMP signaling.

Keywords: BMP; EGF; LRIG1; Quiescence; Stem cell.

Fig. 1

LRIG1 sensitizes cells to BMP signaling. Specifically, LRIG1 (and LRIG3) sensitizes stem cells to BMP signaling through a molecular mechanism that is not yet fully understood. Notably, BMP4 and BMP6 signaling is dependent on LRIG proteins, whereas BMP9 signaling is not [10]. These and other available data have suggested that LRIG1 activity is mediated via BMP type 1 receptor(s) [10, 40]

Fig. 2

LRIG1 marks and regulates quiescent stem cells via its BMP-sensitizing function. The image shows the hypothesized roles played by LRIG1, BMP, and EGF in adult neural stem cell quiescence and proliferation, which is exemplary of the stem cell niches discussed in the text. Similar schemes can be envisioned for the other stem cell compartments discussed. BMPs induce quiescence in activated LRIG1-positive (LRIG1^hi) stem cells, whereas LRIG1-negative (LRIG1^lo) stem cells are largely insensitive to BMP ligands. Quiescent stem cells do not respond to EGF, whereas ‘activated’ stem cells proliferate in response to EGF, thereby forming transit-amplifying progenitor cell populations. Whether and how stem cells transition between the LRIG1^lo and LRIG1^hi states remain unknown