Platelet‐derived growth factor signals play critical roles in differentiation of longitudinal smooth muscle cells in mouse embryonic gut

Abstract

In the development of mouse gut, longitudinal smooth muscle cells (LMC) and interstitial cells of Cajal (ICC) originate from common precursor cells expressing c-Kit. Recently, some gastrointestinal stromal tumours, which develop from smooth muscle layers of the gut and have gain-of-function mutations of c-kit, have been reported to have gain-of-function mutations of platelet-derived growth factor (PDGF) receptor alpha gene. These data raise the possibility that PDGF signalling might be involved in the development of LMC. Therefore, we examined the expression pattern of the PDGF signal family of embryonic gut by immunohistochemistry and in situ hybridization, and investigated the role of PDGF signals in the development of smooth muscle layers in mouse gut using a new organ culture system. During embryonic development, the circular muscle layer expressed PDGF-A, enteric neurons expressed PDGF-B and common precursor cells of LMC and ICC expressed both PDGF receptor alpha and beta. The selective PDGF receptor inhibitor AG1295 suppressed the differentiation of LMC in gut explants. We conclude that PDGF signals play critical roles in the differentiation of LMC in mouse embryonic gut.

Forkhead Box F2 Regulation of Platelet-derived Growth Factor and Myocardin/Serum Response Factor Signaling Is Essential for Intestinal Development

“…The increased expression of PDGF ligands and receptor in Foxf2-deficient colons could thus be stimulating proliferation of the neonatal colonic smooth muscle and/or delaying cell cycle exit. It has been previously shown that PDGF ligands originate from the circular muscle layer and myenteric plexus of the gut, and PDGF receptor ␣ is more highly expressed in the longitudinal muscle than the circular smooth muscle layer (57). This expression pattern could explain why the circular muscle layer is less affected by Foxf2 deletion, because it lacks the receptor to respond to PDGF ligands.…”

“…Expansion of the myenteric plexus in Tg(smMHC-Cre-eGFP ϩ/Ϫ );Foxf2 Ϫ/Ϫ mice was confirmed by immunostaining with antibodies against the platelet-derived growth factor receptor ␣ (PDGF receptor ␣) (Fig. 4G) that is highly expressed in neurons (54 -56) and weakly expressed in smooth muscle cells (57). Consistent with increased PDGF receptor ␣ staining, qRT-PCR analysis showed increased expression of PDGF receptor ␣, as well as its ligands PDGFa and PDGFb, in Tg(smMHC-Cre-eGFP ϩ/Ϫ );Foxf2 Ϫ/Ϫ colons (Fig.…”

“…In addition to expression in enteric neurons, PDGF receptor ␣, and PDGF ligands are expressed in colon smooth muscle (1,57). PDGF has been shown to be a potent mitogenic agent in smooth muscle cells (62), and a cell autonomous role for PDGF signaling in smooth muscle proliferation has been previously demonstrated (63).…”

c-Kit-negative fibroblast-like cells express platelet-derived growth factor receptor α in the murine gastrointestinal musculature

“…The W locus of murine chromosome 5 is the allele of the c-kit gene and several W mutations are known to be spontaneous c-kit gene mutations (Chabot et al 1988;Kitamura et al 2001). Because the c-Kit regulates ICC development by expressing an early stage of precursor cells for smooth muscle cells and ICC (Kluppel et al 1998;Kurahashi et al 2008;Torihashi et al 1997), mutant mice with W mutations show developmental deficiency of ICC in the GI tract. The W/W v mutant mice that are conventionally used as models of loss of c-Kit function have heterozygous c-kit gene mutations and a deficiency in some type of ICC, such as ICC-IM in the stomach or ICC-MY in the small intestine and distal colon (Rumessen and Vanderwinden 2003;Sanders 1996).…”

Determinants of the Epithelial-Muscular Axis on Embryonic Stem Cell-Derived Gut-Like Structures

“…Maturation of both ICCs and gut smooth muscle cells is observed at weeks 8-11, followed by the organization of muscle layers and ICC network in human embryos [25] . The expressions of c-Kit, platelet-derived growth factor, and activin are associated with the differentiation of ICCs or smooth muscle cells [26][27][28][29] . From these reports, a mechanism is suggested to the effect that activin enhances ICC/smooth muscle cell precursor cells.…”