Differential Regional and Subtype-Specific Vulnerability of Enteric Neurons to Mitochondrial Dysfunction

Viader, Andreu; Wright-Jin, Elizabeth C.; Vohra, Bhupinder P.S.; Heuckeroth, Robert O.; Milbrandt, Jeffrey

doi:10.1371/journal.pone.0027727

Cited by 29 publications

(19 citation statements)

References 45 publications

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“…Myenteric and submucosal plexus samples were obtained as described previously (Viader et al, 2011). In the adult mice, sequential 2 cm long samples of myenteric plexus taken from the duodenum (starting at the junction with the pylorus) and distal colon were double-labeled with either biotinylated-anti-HuC/HuD (mouse; polyclonal; 1:250; Invitrogen A21272) and anti-S1003 (rabbit; polyclonal; 1:500; Dako), or NADPH diaphorase (NADPH-d) (Neuhuber et al, 1994) and anti-TuJ1 (rabbit; polyclonal; 1:10,000; Covance).…”

Section: Methodsmentioning

confidence: 99%

Retinaldehyde dehydrogenase enzymes regulate colon enteric nervous system structure and function

Wright-Jin

Grider

Duester

et al. 2013

Developmental Biology

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The enteric nervous system (ENS) forms from neural crest-derived precursors that colonize the bowel before differentiating into a network of neurons and glia that control intestinal function. Retinoids are essential for normal ENS development, but the role of retinoic acid (RA) metabolism in development remains incompletely understood. Because RA is produced locally in tissues where it acts by stimulating RAR and RXR receptors, RA signaling during development is absolutely dependent on the rate of RA synthesis and degradation. RA is produced by three different enzymes called retinaldehyde dehydrogenases (RALDH1, RALDH2 and RALDH3) that are all expressed in developing bowel. To determine the relative importance of these enzymes for ENS development, we analyzed whole mount preparations of adult (8–12 week old) myenteric and submucosal plexus stained with NADPH diaphorase (neurons and neurites), anti-TuJ1 (neurons and neurites), anti-HuC/HuD (neurons), and anti-S1003 (glia) in an allelic series of mice with mutations in Raldh1, Raldh2, and Raldh3. We found that Raldh1−/−, Raldh2+/−, Raldh3+/− (R1KOR2HetR3Het) mutant mice had a reduced colon myenteric neuron density, reduced colon myenteric neuron to glia ratio, reduced colon submucosal neuron density, and increased colon myenteric fibers per neuron when compared to wild type (WT; Raldh1WT, Raldh2WT, Raldh3WT) mice. These defects are unlikely to be due to defective ENS precursor migration since R1KOR2HetR3KO mice had increased enteric neuron progenitor migration into the distal colon compared to WT during development. RALDH mutant mice also have reduced contractility in the colon compared to WT mice. These data suggest that RALDH1, RALDH2 and RALDH3 each contribute to ENS development and function.

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Section: Methodsmentioning

confidence: 99%

Retinaldehyde dehydrogenase enzymes regulate colon enteric nervous system structure and function

Wright-Jin

Grider

Duester

et al. 2013

Developmental Biology

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“…This model, reminiscent of human intestinal pseudo-obstruction, suggests a major role played by mitochondrial dysfunction in neuron and glia degeneration (47).…”

Section: Egc Neuroprotective Functions: Lessons From Enteric Glia Ablmentioning

confidence: 99%

Enteric glia and neuroprotection: basic and clinical aspects

Giorgio

Giancola

Boschetti

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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The enteric nervous system (ENS), a major regulatory system for gastrointestinal function, is composed of neurons and enteric glial cells (EGCs). Enteric glia have long been thought to provide only structural support to neurons. However, recent evidence indicates enteric glia-neuron cross talk significantly contributes to neuronal maintenance, survival, and function. Thus damage to EGCs may trigger neurodegenerative processes thought to play a role in gastrointestinal dysfunctions and symptoms. The purpose of this review is to provide an update on EGCs, particularly focusing on their possible neuroprotective features and the resultant enteric neuron abnormalities subsequent to EGC damage. These neuroprotective mechanisms may have pathogenetic relevance in a variety of functional and inflammatory gut diseases. Basic and clinical (translational) studies support a neuroprotective role mediated by EGCs. Different models have been developed to test whether selective EGC damage/ablation has an impact on gut functions and the ENS. Preclinical data indicated that selective EGC alterations were associated with changes in gut physiology related to enteric neuron abnormalities. In humans, a substantial loss of EGCs was described in patients with various functional and/or inflammatory gastrointestinal diseases. However, whether EGC changes precede or follow neuronal degeneration and loss and how this damage occurs is not defined. Additional studies on EGC neuroprotective capacity are expected to improve knowledge of gut diseases and pave the way for targeted therapeutic strategies of underlying neuropathies. enteric glia; enteric neurons; enteric neuropathy; neuroprotection; neurodegeneration DIGESTION, I.E., THE BREAKDOWN and mixing of food with secretions, nutrient digestion and absorption, propulsion of the contents throughout the gut, and, finally, the expulsion of undigested material, requires a vast repertoire of highly integrated regulatory mechanisms. These are finely tuned by a variety of cell types, including endocrine cells [distributed throughout the gastrointestinal (GI) mucosa], smooth muscle cells (final effectors of contractility and/or relaxation), interstitial cells of Cajal (ICC) (pacemakers of gut motility and regulators of neuromuscular transmission), and neurons of both intrinsic (enteric) and extrinsic (sympathetic and parasympathetic) origin (50). The neural network of the digestive system, including the enteric nervous system (ENS), exerts a prominent regulatory role. From a structural standpoint, the ENS contains about 100 to 500 million neuronal cell bodies organized in two major ganglionated plexuses (i.e., myenteric and submucosal), neural processes connecting the ganglia among them, and nerve fibers targeting many different effector cells. In addition to neurons, enteric glial cells (EGCs) were recently identified as key players in the ENS. EGCs, which form the largest cell population of the ENS, have long been thought to exert a mere mechanical property by supporting neurons (hence the ancient...

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“…However, unlike the CNP promoter, the PLP promoter was recently found to be active in stem cells of the spinal cord (Harlow et al, 2014) (Table 4). The CNP-Cre knock-in (Lappe-Seifke et al, 2003) also shows early activity in Schwann cell precursors at E12 (Genoud et al, 2002), and has been used for gene ablation in OPCs (Genoud et al, 2002), myelinating oligodendrocytes (Brockschnieder et al, 2004; Kaga et al, 2006), Schwann cells (Grigoryan et al, 2013), and even enteric neurons and glia (Viader et al, 2011). The PLP-Cre is available as several tamoxifen-inducible strains (Doerflinger et al, 2003; Leone et al, 2003) for Cre targeting to oligodendroglia and Schwann cells.…”

Section: Genetic Models For Glial-specific Targetingmentioning

confidence: 99%

Finding degrees of separation: Experimental approaches for astroglial and oligodendroglial cell isolation and genetic targeting

Chew¹,

DeBoy²,

Senatorov³

2014

Journal of Neuroscience Methods

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The study of CNS glial cell function requires experimental methods to detect, purify, and manipulate each cell population with fidelity and specificity. With the identification and cloning of cell- and stage-specific markers, glial cell analysis techniques have grown beyond physical methods of tissue dissociation and cell culture, and become highly specific with immunoselection of cell cultures in vitro and genetic targeting in vivo. The unique plasticity of glial cells offers the potential for cell replacement therapies in neurological disease that utilize neural cells derived from transplanted neural stem and progenitor cells. In this mini-review, we outline general physical and genetic approaches for macroglial cell generation. We summarize cell culture methods to obtain astrocytes and oligodendrocytes and their precursors, from developing and adult tissue, as well as approaches to obtain human neural progenitor cells through the establishment of stem cells. We discuss popular targeting rodent strains designed for cell-specific detection, selection and manipulation of neuroglial cell progenitors and their committed progeny. Based on shared markers between astrocytes and stem cells, we discuss genetically modified mouse strains with overlapping expression, and highlight SOX-expressing strains available for targeting of stem and progenitor cell populations. We also include recently established mouse strains for detection, and tag-assisted RNA and miRNA analysis. This discussion aims to provide a brief overview of the rapidly expanding collection of experimental approaches and genetic resources for the isolation and targeting of macroglial cells, their sources, progeny and gene products to facilitate our understanding of their properties and potential application in pathology.

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Differential Regional and Subtype-Specific Vulnerability of Enteric Neurons to Mitochondrial Dysfunction

Cited by 29 publications

References 45 publications

Retinaldehyde dehydrogenase enzymes regulate colon enteric nervous system structure and function

Retinaldehyde dehydrogenase enzymes regulate colon enteric nervous system structure and function

Enteric glia and neuroprotection: basic and clinical aspects

Finding degrees of separation: Experimental approaches for astroglial and oligodendroglial cell isolation and genetic targeting

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