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Retinoic acid regulates murine enteric nervous system precursor proliferation, enhances neuronal precursor differentiation, and reduces neurite growth in vitro.

ABSTRACT: Enteric nervous system (ENS) precursors undergo a complex process of cell migration, proliferation, and differentiation to form an integrated network of neurons and glia within the bowel wall. Although retinoids regulate ENS development, molecular and cellular mechanisms of retinoid effects on the ENS are not well understood. We hypothesized that retinoids might directly affect ENS precursor differentiation and proliferation, and tested that hypothesis using immunoselected fetal ENS precursors in primary culture. We now demonstrate that all retinoid receptors and many retinoid biosynthetic enzymes are present in the fetal bowel at about the time that migrating ENS precursors reach the distal bowel. We further demonstrate that retinoic acid (RA) enhances proliferation of subsets of ENS precursors in a time-dependent fashion and increases neuronal differentiation. Surprisingly, however, enteric neurons that develop in retinoid deficient media have dramatically longer neurites than those exposed to RA. This difference in neurite growth correlates with increased RhoA protein at the neurite tip, decreased Smurf1 (a protein that targets RhoA for degradation), and dramatically decreased Smurf1 mRNA in response to RA. Collectively these data demonstrate diverse effects of RA on ENS precursor development and suggest that altered fetal retinoid availability or metabolism could contribute to intestinal motility disorders.

SUBMITTER: Sato Y

PROVIDER: S-EPMC2586054 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Retinoic acid regulates murine enteric nervous system precursor proliferation, enhances neuronal precursor differentiation, and reduces neurite growth in vitro.

Sato Yoshiharu Y Heuckeroth Robert O RO

Developmental biology 20080520 1

Enteric nervous system (ENS) precursors undergo a complex process of cell migration, proliferation, and differentiation to form an integrated network of neurons and glia within the bowel wall. Although retinoids regulate ENS development, molecular and cellular mechanisms of retinoid effects on the ENS are not well understood. We hypothesized that retinoids might directly affect ENS precursor differentiation and proliferation, and tested that hypothesis using immunoselected fetal ENS precursors i ...[more]

PMID: 18561907

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Project description:Evidence continues to mount concerning the importance of the enteric nervous system (ENS) in controlling numerous intestinal functions in addition to motility and epithelial functions. Nevertheless, little is known concerning the direct participation of the ENS in the inflammatory response of the gut during infectious or inflammatory insults. In the present study we analyzed the ENS response to bacterial lipopolysaccharide, in particular the production of a major proinflammatory cytokine, tumor necrosis factor-alpha (TNF-?).TNF-? expression (measured by qPCR, quantitative Polymerase Chain Reaction) and production (measured by ELISA) were measured in human longitudinal muscle-myenteric plexus (LMMP) and rat ENS primary cultures (rENSpc). They were either treated or not treated with lipopolysaccharide (LPS) in the presence or not of electrical field stimulation (EFS). Activation of extracellular signal-regulated kinase (ERK) and 5'-adenosine monophosphate-activated protein kinase (AMPK) pathways was analyzed by immunocytochemistry and Western blot analysis. Their implications were studied using specific inhibitors (U0126, mitogen-activated protein kinase kinase, MEK, inhibitor and C compound, AMPK inhibitor). We also analyzed toll-like receptor 2 (TLR2) expression and interleukin-6 (IL-6) production after LPS treatment simultaneously with EFS or TNF-?-neutralizing antibody.Treatment of human LMMP or rENSpc with LPS induced an increase in TNF-? production. Activation of the ENS by EFS significantly inhibited TNF-? production. This regulation occurred at the transcriptional level. Signaling analyses showed that LPS induced activation of ERK but not AMPK, which was constitutively activated in rENSpc neurons. Both U0126 and C compound almost completely prevented LPS-induced TNF-? production. In the presence of LPS, EFS inhibited the ERK and AMPK pathways. In addition, we demonstrated using TNF-?-neutralizing antibody that LPS-induced TNF-? production increased TLR2 expression and reduced IL-6 production.Our results show that LPS induced TNF-? production by enteric neurons through activation of the canonical ERK pathway and also in an AMPK-dependent manner. ENS activation through the inhibition of these pathways decreased TNF-? production, thereby modulating the inflammatory response induced by endotoxin.

Dataset Information

Retinoic acid regulates murine enteric nervous system precursor proliferation, enhances neuronal precursor differentiation, and reduces neurite growth in vitro.

Publications

Retinoic acid regulates murine enteric nervous system precursor proliferation, enhances neuronal precursor differentiation, and reduces neurite growth in vitro.

Similar Datasets

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