Histone arginine methylation by Prmt5 is required for lung branching morphogenesis through repression of BMP signaling

Abstract

Branching morphogenesis is essential for the successful development of a functional lung to accomplish its gas exchange function. Although many studies have highlighted requirements for the bone morphogenetic protein (BMP) signaling pathway during branching morphogenesis, little is known about how BMP signaling is regulated. Here, we report that the protein arginine methyltransferase 5 (Prmt5) and symmetric dimethylation at histone H4 arginine 3 (H4R3sme2) directly associate with chromatin of to suppress its transcription. Inactivation of in the lung epithelium results in halted branching morphogenesis, altered epithelial cell differentiation and neonatal lethality. These defects are accompanied by increased apoptosis and reduced proliferation of lung epithelium, as a consequence of elevated canonical BMP-Smad1/5/9 signaling. Inhibition of BMP signaling by Noggin rescues the lung branching defects of mutant Taken together, our results identify a novel mechanism through which Prmt5-mediated histone arginine methylation represses canonical BMP signaling to regulate lung branching morphogenesis.

Regulation of terminal hypertrophic chondrocyte differentiation inPrmt5mutant mice modeling infantile idiopathic scoliosis

“…Consistent with previous observations in Prmt5-deficient limb (Norrie et al, 2016) and lung epithelium (Li et al, 2018) in mouse, we also observed increased ectopic Bmp4 signal in the growth plate of Col2Cre;Prmt5 f/f mutant IVDs at P10 that was not present in controls (Supplemental Fig. 6B, B').…”

“…Loss of Prmt5 in limb bud and lung tissue induces ectopic, elevated Bmp4 expression which is accompanied by increased apoptosis in these tissues (Li et al, 2018;Norrie et al, 2016).…”

“…Given the range of possible molecular functions for PRMT5, it is not surprising that this enzyme plays a role in a number of tissue-specific differentiation pathways, including keratinocytes, muscle, nerve cells and lung differentiation (Calabretta et al, 2018;Chittka et al, 2012;Dacwag et al, 2009;Kanade and Eckert, 2012;Li et al, 2018). In this study, we used conditional mouse genetics coupled with histological and gene expression analyses to establish a novel role for PRMT5 during chondrocyte differentiation for perinatal spine development, modeling infantile IS.…”

The noncanonical BMP signaling pathway plays an important role in club cell regeneration

“…The BMP family members play key roles in lung development and homeostasis . The signal transduction cascade is initiated when BMPs bind to BMP receptor I (BMPRI) and II (BMPRII), which are serine/threonine kinases .…”

“…13,14 The BMP family members play key roles in lung development and homeostasis. 4,[15][16][17][18][19] The signal transduction cascade is initiated when BMPs bind to BMP receptor I (BMPRI) and II (BMPRII), which are serine/threonine kinases. 20 The constitutively active BMPRII then phosphorylates and activates BMPRI, which in turn phosphorylates Smad 1/5/8.…”