Hepatocyte Growth Factor and MET Support Mouse Enteric Nervous System Development, the Peristaltic Response, and Intestinal Epithelial Proliferation in Response to Injury

Avetisyan, Marina; Wang, Hongtao; Schill, Ellen Merrick; Bery, Saya K.; Grider, John R.; Hassell, John A.; Stappenbeck, Thaddeus S.; Heuckeroth, Robert O.

doi:10.1523/jneurosci.5267-14.2015

Cited by 41 publications

(71 citation statements)

References 118 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Met deletion in myenteric plexus neurons demonstrated a marked loss and reduced length of myenteric plexus Met-immunoreactive neurites (49). These mice exhibited more bowel damage and reduced epithelial cell proliferation following dextran sodium sulfate treatment (49).…”

Section: Neuron-specific Metmentioning

confidence: 99%

See 1 more Smart Citation

Biological roles of hepatocyte growth factor‑Met signaling from genetically modified animals (Review)

Kato

2017

biom rep

View full text Add to dashboard Cite

Abstract. Hepatocyte growth factor (HGF) is produced by stromal and mesenchymal cells, and it stimulates epithelial cell proliferation, motility, morphogenesis and angiogenesis in various organs via tyrosine phosphorylation of its cognate receptor, Met. The HGF-Met signaling pathway contributes in a paracrine manner to the development of epithelial organs, exerts regenerative effects on the epithelium, and promotes the regression of fibrosis in numerous organs. Additionally, the HGF-Met signaling pathway is correlated with the biology of cancer types, neurons and immunity. In vivo analyses using genetic modification have markedly increased the profound understanding of the HGF-Met system in basic biology and its clinical applications. HGF and Met knockout (KO) mice are embryonically lethal. Therefore, amino acids in multifunctional docking sites of Met have been exchanged with specific binding motifs for downstream adaptor molecules in order to investigate the signaling potential of the HGF-Met signaling pathway. Conditional Met KO mice were generated using Cre-loxP methodology and characterization of these mice indicated that the HGF-Met signaling pathway is essential in regeneration, protection, and homeostasis in various tissue types and cells. Furthermore, the results of studies using HGF-overexpressing mice have indicated the therapeutic potential of HGF for various types of disease and injury. In the present review, the phenotypes of Met gene-modified mice are summarized. IntroductionHepatocyte growth factor (HGF). HGF was cloned as a growth factor for hepatocytes (1,2), is identical to scatter factor (SF) and was originally discovered as a fibroblast-derived cell motility factor for epithelial cells (3). HGF is located at 7q21, which spans >70 kb in length and consists of 18 exons. It encodes the inactive pre-pro-HGF, a single chain of 728 amino acids (83 kDa), which includes a signal sequence (1-31), a heavy α chain (69 kDa), and a light β chain (34 kDa). The exons encode the α chain, with four kringle structures (highly conserved triple disulfide loop structures), a short spacer region between the α and β chains, and the β chain (Fig. 1A) (4-6).HGF is produced and secreted by adjacent stromal and mesenchymal cells, it contributes to the development of epithelial organs in a paracrine fashion, exerts regenerative effects on epithelia in the liver, kidney, lung, and other tissues, and promotes the regression of fibrosis in numerous organs (7,8). Various growth factors, cytokines, and prostaglandins upregulate HGF gene expression, including basic fibroblast growth factor, oncostatin M, hypoxia-inducible factor 1α and nuclear factor-κB (NF-κB) (9). By contrast, transforming growth factor (TGF)-β1 was demonstrated to markedly downregulate HGF gene expression (10,11).HGF forms a family with HGF-like protein (HLP), a unique protein with a domain structure similar to that of HGF (12). Macrophage stimulating protein (MSP) was discovered as a serum protein that promoted mouse macrophage motility (13) Abbreviatio...

show abstract

Section: Neuron-specific Metmentioning

confidence: 99%

“…In addition, Met was localized to a subset of calcitonin gene-associated peptide-positive myenteric plexus neurons, which are intrinsic primary afferent neurons in the gut (49). Met deletion in myenteric plexus neurons demonstrated a marked loss and reduced length of myenteric plexus Met-immunoreactive neurites (49).…”

Section: Neuron-specific Metmentioning

confidence: 99%

Biological roles of hepatocyte growth factor‑Met signaling from genetically modified animals (Review)

Kato

2017

biom rep

View full text Add to dashboard Cite

show abstract

“…We have used a different approach, examining subgroups for genetic risk by focusing on biomedical phenotypes (Figure 1). The strategy takes advantage of the pleiotropic nature of MET , which, in addition to its role in brain development, has demonstrated functions in systems vulnerable in ASD, including GI (22, 23) and immune (24, 25). The MET ‘ C ’ allele is enriched in children with ASD and co-occurring GID (26) and is associated in mothers who express ASD-associated antibodies that react with fetal brain proteins (27).…”

Section: Genetic Studies: Association Of the Met Tyrosine Kinase Recementioning

confidence: 99%

“…MET signaling is pleiotropic in multiple peripheral organ systems (22–25, 72–74). Here, we describe the role of MET in two systems known to be dysregulated in subpopulations of individuals with ASD: GI and immune.…”

Section: Met the Periphery And Asd: Gi And Immune Functionsmentioning

confidence: 99%

The Pleiotropic MET Receptor Network: Circuit Development and the Neural-Medical Interface of Autism

Eagleson

Levitt

2017

Biological Psychiatry

View full text Add to dashboard Cite

People with autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs) are behaviorally and medically heterogeneous. The combination of polygenicity and gene pleiotropy - the influence of one gene on distinct phenotypes - raises questions of how specific genes and their protein products interact to contribute to NDDs. A preponderance of evidence supports developmental and pathophysiological roles for the MET receptor tyrosine kinase, a multi-functional receptor that mediates distinct biological responses depending upon cell context. MET influences neuron architecture and synapse maturation in the forebrain, and regulates homeostasis in gastrointestinal and immune systems, both commonly disrupted in NDDs. Peak expression of synapse-enriched MET is conserved across rodent and primate forebrain, yet regional differences in primate neocortex are pronounced, with enrichment in circuits that participate in social information processing. A functional risk allele in the MET promoter, enriched in subgroups of children with ASD, reduces transcription and disrupts socially-relevant neural circuits structurally and functionally. In mice, circuit-specific deletion of Met causes distinct atypical behaviors. MET activation increases dendritic complexity and nascent synapse number, but synapse maturation requires reductions in MET. MET mediates its specific biological effects through different intracellular signaling pathways, and has a complex protein interactome that is enriched in ASD and other NDD candidates. The interactome is co-regulated in developing human neocortex. We suggest that a gene as pleiotropic and highly regulated as MET, together with its interactome, is biologically relevant in normal and pathophysiological contexts, impacting central and peripheral phenotypes that contribute to NDD risk and clinical symptoms.

show abstract

“…Interestingly, breast milk reduces occurrence of a deadly bowel disease of premature infants called necrotizing enterocolitis (NEC) (Good et al, 2014). Bowel injury during NEC should further increase translocation of neurotrophic factors and many other breast milk components (e.g., nitrite, L-arginine, glutamine, lactoferrin, or epithelial growth factors) across the epithelium where they may act in concert to prevent further injury and modulate bowel inflammation (Avetisyan et al, 2015b; Gershon, 2012; Savidge et al, 2007; Sigalet et al, 2007). The role of the ENS in NEC is under-investigated, but NEC clearly causes injury to the ENS and transplantation of enteric neural crest-derived stem cells prevents death in an experimental NEC model (Zhou et al, 2013).…”

Section: Evidence That Non-genetic Factors May Alter Ens Structure Wimentioning

confidence: 99%

Gene-environment interactions and the enteric nervous system: Neural plasticity and Hirschsprung disease prevention

Heuckeroth

Schäfer

2016

Developmental Biology

Self Cite

View full text Add to dashboard Cite

Intestinal function is primarily controlled by an intrinsic nervous system of the bowel called the enteric nervous system (ENS). The cells of the ENS are neural crest derivatives that migrate into and through the bowel during early stages of organogenesis before differentiating into a wide variety of neurons and glia. Although genetic factors critically underlie ENS development, it is now clear that many non-genetic factors may influence the number of enteric neurons, types of enteric neurons, and ratio of neurons to glia. These non-genetic influences include dietary nutrients and medicines that may impact ENS structure and function before or after birth. This review summarizes current data about gene-environment interactions that affect ENS development and suggests that these factors may contribute to human intestinal motility disorders like Hirschsprung disease or irritable bowel syndrome.

show abstract

Hepatocyte Growth Factor and MET Support Mouse Enteric Nervous System Development, the Peristaltic Response, and Intestinal Epithelial Proliferation in Response to Injury

Cited by 41 publications

References 118 publications

Biological roles of hepatocyte growth factor‑Met signaling from genetically modified animals (Review)

Biological roles of hepatocyte growth factor‑Met signaling from genetically modified animals (Review)

The Pleiotropic MET Receptor Network: Circuit Development and the Neural-Medical Interface of Autism

Gene-environment interactions and the enteric nervous system: Neural plasticity and Hirschsprung disease prevention

Contact Info

Product

Resources

About