Retinoblastoma protein prevents enteric nervous system defects and intestinal pseudo-obstruction

Ming Fu; Solange Landreville; Olga A Agapova; Luke A Wiley; Michael Shoykhet; J William Harbour; Robert O Heuckeroth

doi:10.1172/JCI67653

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Retinoblastoma protein prevents enteric nervous system defects and intestinal pseudo-obstruction

Journal article

Open access

Peer reviewed

Retinoblastoma protein prevents enteric nervous system defects and intestinal pseudo-obstruction

Ming Fu, Solange Landreville, Olga A Agapova, Luke A Wiley, Michael Shoykhet, J William Harbour and Robert O Heuckeroth

The Journal of clinical investigation, Vol.123(12), pp.5152-5164

12/2013

DOI: 10.1172/JCI67653

PMCID: PMC3859411

PMID: 24177421

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Abstract

The retinoblastoma 1 (RB1) tumor suppressor is a critical regulator of cell cycle progression and development. To investigate the role of RB1 in neural crest-derived melanocytes, we bred mice with a floxed Rb1 allele with mice expressing Cre from the tyrosinase (Tyr) promoter. TyrCre+;Rb1fl/fl mice exhibited no melanocyte defects but died unexpectedly early with intestinal obstruction, striking defects in the enteric nervous system (ENS), and abnormal intestinal motility. Cre-induced DNA recombination occurred in all enteric glia and most small bowel myenteric neurons, yet phenotypic effects of Rb1 loss were cell-type specific. Enteric glia were twice as abundant in mutant mice compared with those in control animals, while myenteric neuron number was normal. Most myenteric neurons also appeared normal in size, but NO-producing myenteric neurons developed very large nuclei as a result of DNA replication without cell division (i.e., endoreplication). Parallel studies in vitro found that exogenous NO and Rb1 shRNA increased ENS precursor DNA replication and nuclear size. The large, irregularly shaped nuclei in NO-producing neurons were remarkably similar to those in progeria, an early-onset aging disorder that has been linked to RB1 dysfunction. These findings reveal a role for RB1 in the ENS.

Myenteric Plexus - pathology

Endoreduplication

Neuroglia - pathology

Cell Count

Humans

Nerve Tissue Proteins - deficiency

Gastrointestinal Motility - physiology

Growth Disorders - etiology

Recombinant Fusion Proteins

Neurons - ultrastructure

Melanocytes - pathology

Progeria

Intestinal Pseudo-Obstruction - prevention & control

Neurons - physiology

Myenteric Plexus - abnormalities

Retinoblastoma Protein - physiology

Disease Models, Animal

Nerve Tissue Proteins - physiology

Genes, Retinoblastoma

DNA Replication

Retinoblastoma Protein - deficiency

Cell Nucleus - ultrastructure

Intestinal Pseudo-Obstruction - genetics

Mice, Knockout

Animals

Intestinal Pseudo-Obstruction - etiology

Mice

Growth Disorders - genetics

Nitric Oxide - metabolism

Details

Title: Subtitle: Retinoblastoma protein prevents enteric nervous system defects and intestinal pseudo-obstruction
Creators: Ming Fu
Solange Landreville
Olga A Agapova
Luke A Wiley
Michael Shoykhet
J William Harbour
Robert O Heuckeroth
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.123(12), pp.5152-5164
DOI: 10.1172/JCI67653
PMID: 24177421
PMCID: PMC3859411
NLM abbreviation: J Clin Invest
ISSN: 0021-9738
eISSN: 1558-8238
Publisher: American Society for Clinical Investigation
Grant note: R01 DK087715 / NIDDK NIH HHS\nR01 DK57038 / NIDDK NIH HHS\nP30 EY02687 / NEI NIH HHS\nK08 NS082362 / NINDS NIH HHS\nR01 EY13169 / NEI NIH HHS\nR01 EY013169 / NEI NIH HHS\nP30 EY002687 / NEI NIH HHS\nR01 DK057038 / NIDDK NIH HHS\nK12 HD076224 / NICHD NIH HHS\nK12-HD076224 / NICHD NIH HHS\nKO8 NS082362-01 / NINDS NIH HHS
Language: English
Date published: 12/2013
Academic Unit: Ophthalmology and Visual Sciences
Record Identifier: 9983979954002771

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