Ncx (Enx, Hox11L.1) is required for neuronal cell death in enteric ganglia of mice

Aoki, Taito; Jusuf, Ahmad Aulia; Iitsuka, Yoshinuri; Isono, Kaichi; Tokuhisa, Takeshi; Hatano, Masahiko

doi:10.1016/j.jpedsurg.2007.01.064

Cited by 10 publications

(12 citation statements)

References 34 publications

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“…The observed neuronal senescence with age in the present study is in agreement with existing data in other species, including humans (54–56), and is associated with a process of “pruning” neurons generated in excess (55, 57). In contrast, enteric neuron numbers in the EWS pig ileum did not decline with age.…”

Section: Discussionsupporting

confidence: 92%

Early life adversity in piglets induces long‐term upregulation of the enteric cholinergic nervous system and heightened, sex‐specific secretomotor neuron responses

Medland

Pohl

Edwards

et al. 2016

Neurogastroenterology Motil

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Background Early life adversity (ELA) is a risk factor for the later-life onset of gastrointestinal (GI) diseases such as irritable bowel syndrome (IBS); however, the mechanisms are poorly understood. Here, we utilized a porcine model of ELA, early weaning stress (EWS), to investigate the influence of ELA on the development and function of the enteric nervous system (ENS). Methods Female and castrated male (Male-C) piglets were weaned from their sow either at 15 d of age (EWS) or 28 d of age (late weaning control; LWC). At 60 d and 170 d of age, ileal mucosa-submucosa preparations were mounted in Ussing chambers and veratridine- and corticotropin releasing factor (CRF)-evoked short circuit current (Isc) responses were recorded as indices of secretomotor neuron function. Enteric neuron numbers and the expression of select neurotransmitters and their receptors were also measured. Key Results Compared with LWC pigs, female, but not Male-C EWS pigs exhibited heightened veratridine-induced Isc responses at 60 d and 170 d of age, that were blocked with tetrodotoxin (TTX) and atropine. Ileum from EWS pigs had higher numbers of enteric neurons that were choline acetyltransferase-positive (ChAT+). Markers of increased cholinergic signaling (increased acetylcholinesterase (AchE) and down-regulated mucosal muscarinic receptor 3 gene expression were also observed in EWS pigs. Conclusions & Inferences This study demonstrated that EWS in pigs induces lasting and sex-specific hypersensitivity of secretomotor neuron function and upregulation of the cholinergic ENS. These findings may represent a mechanistic link between ELA and lifelong susceptibility to GI diseases such as IBS.

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Section: Discussionsupporting

confidence: 92%

Early life adversity in piglets induces long‐term upregulation of the enteric cholinergic nervous system and heightened, sex‐specific secretomotor neuron responses

Medland

Pohl

Edwards

et al. 2016

Neurogastroenterology Motil

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“…The observations reported by Aoki et al (2007) are intriguing in that they indicate that although substantial neuronal death may not occur in the fetal ENS, it does take place post-natally. If these findings can be confirmed, they would support the idea that the ENS is indeed subject to pruning of neuronal numbers by cell death, but that this process does not substantially commence until after birth.…”

Section: Discussionmentioning

confidence: 96%

“…Such knockout mice develop a megacolon and by 2–6 weeks after birth (but not at birth) have far more neurons in the proximal colon as well as other areas of the ENS compared with WT mice. Because they did not detect increased post-natal birth of ENS neurons in the mutant mice, Aoki et al (2007) suggested that the neuronal hyperplasia was due to a deficiency in cell death. In consonance with this, P7 Ncx/Hox11L1 knockout mice showed little TUNEL staining in the P7 ENS when compared with their WT controls.…”

Section: Cell Death and The Developing Ensmentioning

confidence: 95%

“…Aoki et al (2007) reported extensive TUNEL labeling of enteric neurons in the proximal colon of P7 mice. Moreover, counts of enteric neurons (identified by staining with cuprolinic blue) in the proximal colon revealed that their numbers decreased by about 2-fold between birth and 4 weeks of age.…”

Section: Cell Death and The Developing Ensmentioning

confidence: 99%

“…Moreover, counts of enteric neurons (identified by staining with cuprolinic blue) in the proximal colon revealed that their numbers decreased by about 2-fold between birth and 4 weeks of age. Aoki et al (2007) also examined TUNEL labeling in P7 mice null for expression of Ncx/Hox11L1 , a gene that appears to be involved in the specification of neural lineage among ENCDCs. Such knockout mice develop a megacolon and by 2–6 weeks after birth (but not at birth) have far more neurons in the proximal colon as well as other areas of the ENS compared with WT mice.…”

Section: Cell Death and The Developing Ensmentioning

confidence: 99%

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Cell death and the developing enteric nervous system

Chalazonitis¹,

Gershon²,

Greene³

2012

Neurochemistry International

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This review discusses current knowledge about cell death in the developing enteric nervous system (ENS). It also includes findings about the molecular mechanisms by which such death is mediated. Additional consideration is given to trophic factors that contribute to survival of the precursors and neurons and glia of the ENS, as well to genes that, when mutated or deleted, trigger their death. Although further confirmation is needed, present observations support the view that enteric neural crest-derived precursor cells en route to the gut undergo substantial levels of apoptotic death, but that once these cells colonize the gut, there is relatively little death of precursor cells or of neurons and glia during the fetal period. There are also indications that normal neuron loss occurs in the ENS, but at times beyond the perinatal stage. Taken together, these findings suggest that ENS development is similar is some ways, but different in others from extra-enteric areas of the vertebrate central and peripheral nervous systems, in which large-scale apoptotic death of precursor neurons and glia occurs during the fetal and perinatal periods. Potential reasons for these differences are discussed such as a fetal enteric microenvironment that is especially rich in trophic support. In addition to the cell death that occurs during normal ENS development, this review discusses mechanisms of experimentally-induced ENS cell death, such as those that are associated with defective glial cell-line derived neurotrophic factor/Ret signaling, which are an animal model of human congenital megacolon (aganglionosis; Hirschsprung's disease). Such considerations underscore the importance of understanding cell death in the developing ENS, not just from a curiosity-driven point of view, but also because the pathophysiology behind many disorders of human gastrointestinal function may originate in abnormalities of the mechanisms that govern cell survival and death during ENS development.

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Immature enteric neurons in Ncx/Hox11L.1 deficient intestinal neuronal dysplasia model mice

et al. 2009

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Ncx (Enx, Hox11L.1) is required for neuronal cell death in enteric ganglia of mice

Cited by 10 publications

References 34 publications

Early life adversity in piglets induces long‐term upregulation of the enteric cholinergic nervous system and heightened, sex‐specific secretomotor neuron responses

Early life adversity in piglets induces long‐term upregulation of the enteric cholinergic nervous system and heightened, sex‐specific secretomotor neuron responses

Cell death and the developing enteric nervous system

Immature enteric neurons in Ncx/Hox11L.1 deficient intestinal neuronal dysplasia model mice

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