CoChat
Sign Up
Cited by 47Congenital gastrointestinal and neural anomaliesGastrointestinal motility and disordersNeurogenesis and neuroplasticity mechanisms

Expression Level of Hand2 Affects Specification of Enteric Neurons and Gastrointestinal Function in Mice

Open access
D'Autréaux, Fabien, Margolis, Kara G., Roberts, Jane, Stevanovic, Korey, Mawe, Gary, Li, Zhishan, Karamooz, Nima, Ahuja, Ankur +4 more·2011·Gastroenterology
DOI 10.1053/j.gastro.2011.04.059PMC PMC3152642
Open this paper in CoChat — free account

Abstract

Background & aims Hand2 is a basic helix-loop-helix transcription factor required for terminal differentiation of enteric neurons. We studied Hand2 haploinsufficient mice, to determine whether reduced expression of Hand2 allows sufficient enteric neurogenesis for survival, but not for development of a normal enteric nervous system (ENS). Methods Enteric transcripts that encode Hand2 and the neuron-specific embryonic lethal abnormal vision proteins HuB, HuC, and HuD were quantified. Immunocytochemistry was used to identify and quantify neurons. Apoptosis was analyzed with the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling procedure. Intracellular microelectrodes were used to record inhibitory junction potentials. Gastrointestinal transit and colonic motility were measured in vivo. Results Levels of of enteric Hand2 transcripts were associated with genotypes of mice, in the following order: Hand2(+/+) > Hand2(LoxP/+) > Hand2(+/-) > Hand2(LoxP/-). Parallel reductions were found in expression of HuD and in regional and phenotypic manners. Numbers of neurons, numbers of neuronal nitric oxide synthase(+) and calretinin(+), but not substance P(+) or vasoactive intestinal peptide(+) neurons, decreased. No effects were observed in stomach or cecum. Apoptosis was not detected, consistent with the concept that Hand2 inhibits neuronal differentiation, rather than regulates survival. The amplitude of inhibitory junction potentials in colonic circular muscle was similar in Hand2 wild-type and haploinsufficient mice, although in haploinsufficient mice, the purinergic component was reduced and a nitrergic component appeared. The abnormal ENS of haploinsufficient mice slowed gastrointestinal motility but protected mice against colitis. Conclusions Reduced expression of factors required for development of the ENS can cause defects in the ENS that are subtle enough to escape detection yet cause significant abnormalities in bowel function.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1053/j.gastro.2011.04.059

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In the adult mouse and rodent nervous system, HuD mRNA expression is mostly restricted to specific neuronal populations, including large pyramidal-like neurons in layer V of the neocortex and cerebellar cortex (Purkinje cells), the four Cornu Amonis (CA1-4) regions of the hippocampus, dorsal root ganglia, motor neurons in the spinal cord, mitral cells in the olfactory bulb, ganglion and internal P

    “In the adult mouse and rodent nervous system, expression of HuD mRNA is mostly restricted to specific neuronal populations, including large pyramidal-like neurons in layer V of the neocortex and cerebellar cortex (Purkinje cells), the four Cornu Amonis (CA1-4) regions of the hippocampus, dorsal root ganglia, and motor neurons in the spinal cord, mitral cells in the olfactory bulb, ganglion and int”

    From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as D’Autreaux et al. 2011

    The Methods and Results (page unavailable) describe HuD as neuron-specific and report its expression in the mouse enteric nervous system. They do not describe the claimed restriction of HuD mRNA to the listed brain regions, dorsal root ganglia, or spinal motor neurons. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 35

  1. [1]Firulli AB A HANDful of questions: the molecular biology of the heart and neural crest derivatives (HAND)-subclass of basic helix-loop-helix transcription factors Gene 2003 312 27 40 12909338
  2. [2]Hendershot TJ Liu H Sarkar AA Giovannucci DR Clouthier DE Abe M Howard MJ Expression of Hand2 is sufficient for neurogenesis and cell type-specific gene expression in the enteric nervous system Dev Dyn 2007 236 93 105 17075884
  3. [3]D’Autreaux F Morikawa Y Cserjesi P Gershon MD Hand2 is necessary for terminal differentiation of enteric neurons from crest-derived precursors but not for their migration into the gut or for formation of glia Development 2007 134 2237 49 17507395
  4. [4]Morikawa Y D’Autreaux F Gershon MD Cserjesi P Hand2 determines the noradrenergic phenotype in the mouse sympathetic nervous system Dev Biol 2007 307 114 26 17531968 PMC1952239
  5. [5]Chalazonitis A D’Autreaux F Guha U Pham TD Faure C Chen JJ Roman D Kan L Rothman TP Kessler JA Gershon MD Bone morphogenetic protein-2 and -4 limit the number of enteric neurons but promote development of a TrkC-expressing neurotrophin-3-dependent subset J. Neurosci 2004 24 4266 4282 15115823 PMC6729284
  6. [6]Comoletti D Flynn RE Boucard AA Demeler B Schirf V Shi J Jennings LL Newlin HR Sudhof TC Taylor P Gene selection, alternative splicing, and post-translational processing regulate neuroligin selectivity for beta-neurexins Biochemistry 2006 45 12816 27 17042500
  7. [7]Karnovsky MJ Roots L A “direct-coloring” method thiocholine method for cholinesterases J Histochem Cytochem 1964 12 219 221 14187330
  8. [8]Castagliuolo I Morteau O Keates AC Valenick L Wang CC Zacks J Lu B Gerard NP Pothoulakis C Protective effects of neurokinin-1 receptor during colitis in mice: role of the epidermal growth factor receptor Br J Pharmacol 2002 136 271 9 12010776 PMC1573337
  9. [9]Cooper HS Murthy SN Shah RS Sedergran DJ Clinicopathologic study of dextran sulfate sodium experimental murine colitis Lab Invest 1993 69 238 49 8350599
  10. [10]Sang Q Young H Chemical coding of neurons in the myenteric plexus and external muscle of the small and large intestine of the mouse Cell Tiss. Res 1996 284 39 53 8601295
  11. [11]Pham TD Gershon MD Rothman TP Time of origin of neurons in the murine enteric nervous system J. Comp. Neurol 1991 314 789 798 1816276
  12. [12]Chalazonitis A Pham TD Li Z Roman D Guha U Gomes W Kan L Kessler JA Gershon MD Bone morphogenetic protein regulation of enteric neuronal phenotypic diversity: relationship to timing of cell cycle exit J Comp Neurol 2008 509 474 92 18537141 PMC2592098
  13. [13]Hao MM Moore RE Roberts RR Nguyen T Furness JB Anderson RB Young HM The role of neural activity in the migration and differentiation of enteric neuron precursors Neurogastroenterol Motil 2010 22 127 137 20082666
  14. [14]Branchek TA Gershon MD Time course of expression of neuropeptide Y, calcitonin gene related peptide, and NADPH diaphorase activity in neurons of the developing murine bowel and the appearance of 5-hydroxytryptamine in mucosal enterochromaffin cells J. Comp. Neurol 1989 285 262 273 2788179
  15. [15]Young HM Jones BR McKeown SJ The projections of early enteric neurons are influenced by the direction of neural crest cell migration J Neurosci 2002 22 6005 18 12122062 PMC6757928
  16. [16]Rothman TP Nilaver G Gershon MD Colonization of the developing murine enteric nervous system and subsequent phenotypic expression by the precursors of peptidergic neurons J. Comp. Neurol 1984 225 13 23 6202725
  17. [17]Fontaine-Pérus JC Chanconie M Le Douarin NM Differentiation of peptidergic neurons in quail-chick chimeric embryos Cell Differ 1982 11 183 193 6180836
  18. [18]Nagakura Y Naitoh Y Kamato T Yamano M Miyata K Compounds possessing 5-HT3 receptor antagonistic activity inhibit intestinal propulsion in mice Eur J Pharmacol 1996 311 67 72 8884238
  19. [19]Hwang SJ O’Kane N Singer C Ward SM Sanders KM Koh SD Block of inhibitory junction potentials and TREK-1 channels in murine colon by Ca2+ store-active drugs J Physiol 2008 586 1169 84 18187470 PMC2375637
  20. [20]Spencer NJ Bywater RA Holman ME Taylor GS Spontaneous and evoked inhibitory junction potentials in the circular muscle layer of mouse colon J Auton Nerv Syst 1998 69 115 21 9696266
  21. [21]Serio R Alessandro M Zizzo MG Tamburello MP Mule F Neurotransmitters involved in the fast inhibitory junction potentials in mouse distal colon Eur J Pharmacol 2003 460 183 90 12559380
  22. [22]Powell DW Neuroimmunophysiology of the gastrointestinal mucosa: implications for inflammatory diseases Trans Am Clin Climatol Assoc 1995 106 124 38 discussion 138-40 7483168 PMC2376525
  23. [23]Lawrance IC Wu F Leite AZ Willis J West GA Fiocchi C Chakravarti S A murine model of chronic inflammation-induced intestinal fibrosis down-regulated by antisense NF-kappa B Gastroenterology 2003 125 1750 61 14724828
  24. [24]Akamatsu W Fujihara H Mitsuhashi T Yano M Shibata S Hayakawa Y Okano HJ Sakakibara S Takano H Takano T Takahashi T Noda T Okano H The RNA-binding protein HuD regulates neuronal cell identity and maturation Proc Natl Acad Sci U S A 2005 102 4625 30 15764704 PMC555491
  25. [25]Sakakibara S Okano H Expression of neural RNA-binding proteins in the postnatal CNS: implications of their roles in neuronal and glial cell development J Neurosci 1997 17 8300 12 9334405 PMC6573750
  26. [27]Szabo A Dalmau J Manley G Rosenfeld M Wong E Henson J Posner JB Furneaux HM HuD, a paraneoplastic encephalomyelitis antigen, contains RNA-binding domains and is homologous to Elav and Sex-lethal Cell 1991 67 325 33 1655278
  27. [28]Bakheet T Williams BR Khabar KS ARED 3.0: the large and diverse AU-rich transcriptome Nucleic Acids Res 2006 34 D111 4 16381826 PMC1347415
  28. [29]Gianino S Grider JR Cresswell J Enomoto H Heuckeroth RO GDNF availability determines enteric neuron number by controlling precursor proliferation Development 2003 130 2187 98 12668632
  29. [30]Uesaka T Jain S Yonemura S Uchiyama Y Milbrandt J Enomoto H Conditional ablation of GFRalpha1 in postmigratory enteric neurons triggers unconventional neuronal death in the colon and causes a Hirschsprung’s disease phenotype Development 2007 134 2171 81 17507417
  30. [31]McGuckin MA Eri R Simms LA Florin TH Radford-Smith G Intestinal barrier dysfunction in inflammatory bowel diseases Inflamm Bowel Dis 2009 15 100 13 18623167
  31. [32]Packey CD Sartor RB Commensal bacteria, traditional and opportunistic pathogens, dysbiosis and bacterial killing in inflammatory bowel diseases Curr Opin Infect Dis 2009 22 292 301 19352175 PMC2763597
  32. [33]Margolis KG Gershon MD Neuropeptides and inflammatory bowel disease Curr Opin Gastroenterol 2009 25 503 11 19816171
  33. [34]Knowles CH De Giorgio R Kapur RP Bruder E Farrugia G Geboes K Gershon MD Hutson J Lindberg G Martin JE Meier-Ruge WA Milla PJ Smith VV Vandervinden JM Veress B Wedel T Gastrointestinal neuromuscular pathology: guidelines for histological techniques and reporting on behalf of the Gastro 2009 International Working Group Acta Neuropathol 2009 118 271 301 19360428
  34. [35]Faussone-Pellegrini MS Infantino A Matini P Masin A Mayer B Lise M Neuronal anomalies and normal muscle morphology at the hypomotile ileocecocolonic region of patients affected by idiopathic chronic constipation Histol Histopathol 1999 14 1119 34 10506928
  35. [36]Wattchow D Brookes S Murphy E Carbone S de Fontgalland D Costa M Regional variation in the neurochemical coding of the myenteric plexus of the human colon and changes in patients with slow transit constipation Neurogastroenterol Motil 2008 20 1298 305 18662329

Cited by

Sorted by citations

Authors
D'Autréaux, F., Margolis, K. G., Roberts, J., Stevanovic, K., Mawe, G., Li, Z., Karamooz, N., Ahuja, A., Morikawa, Y., Cserjesi, P., Setlick, W., & Gershon, M. D.
Affiliations
  • Morgan Stanley Children's Hospital (US)
  • University of Vermont (US)
  • Columbia University (US)
  • Tulane University (US)
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2011-08
Volume
141
Issue
2
Pages
576-587.e6
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2011.04.059
PMC
PMC3152642
OpenAlex
W2163317958
Cited by
47
References
1
Citations by year
2026: 1 · 2025: 5 · 2024: 4 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 5 · 2016: 6 · 2015: 1 · 2014: 2 · 2013: 7 · 2012: 3
FWCI
4.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5r01ns015547-39)
  • National Institute of Neurological Disorders and Stroke (R01NS012969, NS12969, R01-NS015547, NS 15547)
Topics
  • Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
Hand2, enteric nervous system, enteric neurogenesis, haploinsufficiency, bHLH transcription factors, HUD, neuronal differentiation, gastrointestinal motility, colonic motility, inhibitory junction potentials, colitis, neuronal apoptosis, neuronal nitric oxide synthase, calretinin
MeSH terms
ELAV-Like Protein 2, ELAV-Like Protein 3, ELAV-Like Protein 4, Animals, Cell Count, Colitis, Colon, Gastrointestinal Motility, Genotype, Intercellular Junctions, Muscle, Smooth, Synaptic Transmission, Neuroglia, Neurons, Substance P, Trinitrobenzenesulfonic Acid, Vasoactive Intestinal Peptide, Apoptosis, Enteric Nervous System, Nitric Oxide Synthase, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, ELAV Proteins, S100 Calcium Binding Protein G, Calbindin 2

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review