Abstract:Chronic intestinal pseudo-obstruction (CIP) in paediatric patients is due to heterogeneous aetiologies that include primary disorders of the enteric nervous system. These conditions are poorly delineated by contemporary diagnostic approaches, in part because the complex nature of the enteric nervous system may shelter significant physiological defects behind subtle or quantitative anatomical changes. Until recently, relatively few experimental animal models existed for paediatric CIP. However, the availability… Show more
“…CIPO includes at least 2 disorders: IND B and GNM (6). IND B is a human congenital disorder consisting of hyperplasia of the submucosa plexus and formation of giant ganglia, without hypertrophy of ENS cells.…”
Section: Importance Of the Pi3k/pten-akt-s6k And Mapk/erk Signaling Pmentioning
confidence: 99%
“…There are multiple forms and classifications of CIPO, but all are associated with neuronal or muscular defects. Disorders of neuronal density (aganglionosis, hypoganglionosis, or hyperganglionosis) have been associated with a neuronal form of CIPO (6).…”
Intestinal ganglioneuromatosis is a benign proliferation of nerve ganglion cells, nerve fibers, and supporting cells of the enteric nervous system (ENS) that can result in abnormally large enteric neuronal cells (ENCs) in the myenteric plexus and chronic intestinal pseudoobstruction (CIPO). As phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a phosphatase that is critical for controlling cell growth, proliferation, and death, we investigated the role of PTEN in the ENS by generating mice with an embryonic, ENC-selective deletion within the Pten locus. Mutant mice died 2 to 3 weeks after birth, with clinical signs of CIPO and hyperplasia and hypertrophy of ENCs resulting from increased activity of the PI3K/PTEN-AKT-S6K signaling pathway. Further analysis revealed that PTEN was only expressed in developing mouse embryonic ENCs from E15.5 and that the rate of ENC proliferation decreased once PTEN was expressed. Specific deletion of the Pten gene in ENCs therefore induced hyperplasia and hypertrophy in the later stages of embryogenesis. This phenotype was reversed by administration of a pharmacological inhibitor of AKT. In some human ganglioneuromatosis forms of CIPO, PTEN expression was found to be abnormally low and S6 phosphorylation increased. Our study thus reveals that loss of PTEN disrupts development of the ENS and identifies the PI3K/PTEN-AKT-S6K signaling pathway as a potential therapeutic target for ganglioneuromatosis forms of CIPO.
IntroductionThe enteric nervous system (ENS) regulates peristalsis, secretions, blood supply, and immune responses in the intestinal tract (1). The mammalian ENS is composed of a large number of neurons and glia that are organized into enteric ganglia distributed throughout the gut wall (2). ENS cells cluster into 2 plexi: the myenteric plexus develops first and is situated between the inner circular and outer longitudinal layers of the muscularis propia; the submucosal plexus forms later during gestation and is positioned between the muscularis propia and the muscularis mucosa (3).Neural crest cells develop from the dorsal part of the neural tube of embryos. They migrate into most of the peripheral regions to produce various derivatives including skin melanocytes and the ENS. In the vagal region, the ENS progenitors, enteric neural crest-derived cells (ENCCs), and their derivatives proliferate actively to expand the relatively small pool of progenitors that invade the foregut; they thereby generate the millions of enteric neurons and glia that are present in the adult intestine (4). A fully colonized gut, with the appropriate number of neuronal and glial cells, is required for integrated peristaltic activity of the gut wall.Many pediatric consultations are due to ENS disorders resulting from a number of neurocristopathies (5). Chronic intestinal pseudoobstruction (CIPO) is a rare, severe, and disabling disorder characterized by repetitive episodes or continuous symptoms of bowel obstruction; it is associated with substantial morbidity and mortality. There ar...
“…CIPO includes at least 2 disorders: IND B and GNM (6). IND B is a human congenital disorder consisting of hyperplasia of the submucosa plexus and formation of giant ganglia, without hypertrophy of ENS cells.…”
Section: Importance Of the Pi3k/pten-akt-s6k And Mapk/erk Signaling Pmentioning
confidence: 99%
“…There are multiple forms and classifications of CIPO, but all are associated with neuronal or muscular defects. Disorders of neuronal density (aganglionosis, hypoganglionosis, or hyperganglionosis) have been associated with a neuronal form of CIPO (6).…”
Intestinal ganglioneuromatosis is a benign proliferation of nerve ganglion cells, nerve fibers, and supporting cells of the enteric nervous system (ENS) that can result in abnormally large enteric neuronal cells (ENCs) in the myenteric plexus and chronic intestinal pseudoobstruction (CIPO). As phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a phosphatase that is critical for controlling cell growth, proliferation, and death, we investigated the role of PTEN in the ENS by generating mice with an embryonic, ENC-selective deletion within the Pten locus. Mutant mice died 2 to 3 weeks after birth, with clinical signs of CIPO and hyperplasia and hypertrophy of ENCs resulting from increased activity of the PI3K/PTEN-AKT-S6K signaling pathway. Further analysis revealed that PTEN was only expressed in developing mouse embryonic ENCs from E15.5 and that the rate of ENC proliferation decreased once PTEN was expressed. Specific deletion of the Pten gene in ENCs therefore induced hyperplasia and hypertrophy in the later stages of embryogenesis. This phenotype was reversed by administration of a pharmacological inhibitor of AKT. In some human ganglioneuromatosis forms of CIPO, PTEN expression was found to be abnormally low and S6 phosphorylation increased. Our study thus reveals that loss of PTEN disrupts development of the ENS and identifies the PI3K/PTEN-AKT-S6K signaling pathway as a potential therapeutic target for ganglioneuromatosis forms of CIPO.
IntroductionThe enteric nervous system (ENS) regulates peristalsis, secretions, blood supply, and immune responses in the intestinal tract (1). The mammalian ENS is composed of a large number of neurons and glia that are organized into enteric ganglia distributed throughout the gut wall (2). ENS cells cluster into 2 plexi: the myenteric plexus develops first and is situated between the inner circular and outer longitudinal layers of the muscularis propia; the submucosal plexus forms later during gestation and is positioned between the muscularis propia and the muscularis mucosa (3).Neural crest cells develop from the dorsal part of the neural tube of embryos. They migrate into most of the peripheral regions to produce various derivatives including skin melanocytes and the ENS. In the vagal region, the ENS progenitors, enteric neural crest-derived cells (ENCCs), and their derivatives proliferate actively to expand the relatively small pool of progenitors that invade the foregut; they thereby generate the millions of enteric neurons and glia that are present in the adult intestine (4). A fully colonized gut, with the appropriate number of neuronal and glial cells, is required for integrated peristaltic activity of the gut wall.Many pediatric consultations are due to ENS disorders resulting from a number of neurocristopathies (5). Chronic intestinal pseudoobstruction (CIPO) is a rare, severe, and disabling disorder characterized by repetitive episodes or continuous symptoms of bowel obstruction; it is associated with substantial morbidity and mortality. There ar...
“…Hirschsprung's disease) (Martucciello et al, 2000;Skinner, 1996). Although Hirschsprung's disease is the most dramatic example of disordered intestinal motility that results from abnormal ENS morphogenesis, more subtle changes in ENS structure also cause altered intestinal motility (De Giorgio et al, 2000;Kapur, 2001). This includes hypo-and hyperganglionosis (Shirasawa et al, 1997;Yamataka et al, 2001), as well as the loss of specific neuronal subpopulations (Blaugrund et al, 1996).…”
To clarify the role of Ret signaling components in enteric nervous system (ENS) development, we evaluated ENS anatomy and intestinal contractility in mice heterozygous for Ret, GFRα1 and Ret ligands. These analyses demonstrate that glial cell line-derived neurotrophic factor (GDNF) and neurturin are important for different aspects of ENS development. Neurturin is essential for maintaining the size of mature enteric neurons and the extent of neuronal projections, but does not influence enteric neuron number. GDNF availability determines enteric neuron number by controlling ENS precursor proliferation. However, we were unable to find evidence of programmed cell death in the wild type ENS by immunohistochemistry for activated caspase 3. In addition, enteric neuron number is normal in Bax -/-and Bid -/-mice, suggesting that, in contrast to most of the rest of the nervous system, programmed cell death is not important for determining enteric neuron numbers. Only mild reductions in neuron size and neuronal fiber counts occur in Ret +/-and Gfra1 +/-mice. All of these heterozygous mice, however, have striking problems with intestinal contractility and neurotransmitter release, demonstrating that Ret signaling is critical for both ENS structure and function.
“…Therefore, any developmental anomalies associated with PKA inhibition must be subtle, possibly including changes in neurochemical coding, synaptic connections, or other aspects of neural circuitry that would not be resolved by our analyses. In this respect, our models contrast with many other murine genetic models of lethal intestinal dysmotility, which are characterized by aganglionosis, hypoganglionosis, or obvious anatomical perturbations of the myenteric plexus (Kapur, 2001;Newgreen and Young, 2002a,b). Some of the latter are caused by mutations that disrupt components of the Indian hedgehog-, Ret-, and Ednrb-mediated intercellular signaling to enteric neural precursors and, in at least some experimental systems, PKA has been implicated as a signal transduction component for each of these pathways (Fuchs et al, 2001;Remy et al, 2001;Fukuda et al, 2002;Barlow et al, 2003).…”
Section: Discussionmentioning
confidence: 95%
“…Although several other genetic rodent models of gastrointestinal dysmotility have been described (Kapur, 2001), the pathology in our mice is unusual in that the proximal small intestine is so profoundly and consistently affected. Other models, particularly those associated with primary neuropathies, are associated with colonic or cecal distension, in some cases Kapur et al (2005).…”
Section: Potential Neurophysiological Functions Of Pkamentioning
A number of in vitro studies suggest that many important developmental and functional events in the enteric nervous system are regulated by the intracellular signaling enzyme cAMP protein kinase A (PKA). To evaluate the in vivo significance of these observations, a Cre-inducible, dominant-negative, mutant regulatory subunit (RIalphaB) of PKA was activated in enteric neurons by either a Proteolipid protein-Cre transgene or a Hox11L1-Cre "knock-in" allele. In both models, RIalphaB activation resulted consistently in profound distension of the proximal small intestine within 2 weeks after birth. Intestinal transit of radio-opaque tracers was severely retarded in the double-transgenic animals, which died shortly after weaning. In the enteric nervous system, recombination was restricted to neurons as demonstrated by histochemical analysis and confocal microscopic colocalization of a Cre recombinase-dependent reporter gene with the neuronal marker Hu(C/D), in contrast with the glial marker S100. Histochemical analysis of beta-galactosidase expression and acetylcholinesterase activity, as well as neuronal counts, demonstrated that intestinal dysmotility was not associated with obvious malformation of the myenteric plexus. However, inhibition of PKA activity in enteric neurons disrupted the major motor complexes of isolated intestinal segments in vitro. These results provide strong evidence that PKA activity plays a critical role in enteric neurotransmission in vivo, and highlight neuronal PKA or related signaling molecules as potential therapeutic targets in gastrointestinal motility disorders.
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