The RNA-binding protein RBPMS2 regulates development of gastrointestinal smooth muscle.
OBJECTIVE
Gastrointestinal development requires regulated differentiation of visceral smooth muscle cells (SMCs) and their contractile activities; alterations in these processes might lead to gastrointestinal neuromuscular disorders. Gastrointestinal SMC development and remodeling involves post-transcriptional modification of messenger RNA. We investigated the function of the RNA-binding protein for multiple splicing 2 (RBPMS2) during normal development of visceral smooth muscle in chicken and expression of its transcript in human pathophysiological conditions.


METHODS
We used avian replication-competent retroviral misexpression approaches to analyze the function of RBPMS2 in vivo and in primary cultures of chicken SMCs. We analyzed levels of RBPMS2 transcripts in colon samples from pediatric patients with Hirschsprung's disease and patients with chronic pseudo obstruction syndrome (CIPO) with megacystis.


RESULTS
RBPMS2 was expressed strongly during the early stage of visceral SMC development and quickly down-regulated in differentiated and mature SMCs. Misexpression of RBPMS2 in differentiated visceral SMCs induced their dedifferentiation and reduced their contractility by up-regulating expression of Noggin, which reduced activity of bone morphogenetic protein. Visceral smooth muscles from pediatric patients with CIPO expressed high levels of RBPMS2 transcripts, compared with smooth muscle from patients without this disorder.


CONCLUSIONS
Expression of RBPMS2 is present in visceral SMC precursors. Sustained expression of RBPMS2 inhibits the expression of markers of SMC differentiation by inhibiting bone morphogenetic protein activity, and stimulates SMC proliferation. RBPMS2 transcripts are up-regulated in patients with CIPO; alterations in RBPMS2 function might be involved in digestive motility disorders, particularly those characterized by the presence of muscular lesions (visceral myopathies).
INSERM U1046, Université Montpellier 1, Université Montpellier 2, Montpellier, France.
Cécile
C
Notarnicola
INSERM U1046, Université Montpellier 1, Université Montpellier 2, Montpellier, France; CHRU Montpellier, Service d'Anatomie Pathologique, Montpellier, France.
Caroline
C
Rouleau
INSERM U1046, Université Montpellier 1, Université Montpellier 2, Montpellier, France.
Ludovic
L
Le Guen
INSERM U1046, Université Montpellier 1, Université Montpellier 2, Montpellier, France.
Anne
A
Virsolvy
INSERM U1046, Université Montpellier 1, Université Montpellier 2, Montpellier, France.
Sylvain
S
Richard
INSERM U1046, Université Montpellier 1, Université Montpellier 2, Montpellier, France.
Sandrine
S
Faure
INSERM U1046, Université Montpellier 1, Université Montpellier 2, Montpellier, France. Electronic address: pascal.de-santa-barbara@inserm.fr.
Pascal
P
De Santa Barbara
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002642:Chick Embryo; D003106:Colon / Q000378:metabolism* / Q000503:physiopathology; D003112:Colonic Pseudo-Obstruction / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005769:Gastrointestinal Motility; D018507:Gene Expression Regulation, Developmental; D005895:Gizzard, Avian / Q000196:embryology / Q000378:metabolism*; D006627:Hirschsprung Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007223:Infant; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000196:embryology / Q000378:metabolism* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D000099176:Noggin Protein
D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D016601:RNA-Binding Proteins; D000099176:Noggin Protein; C101827:RBPMS protein, human; C000593221:RBPMS2 protein, human