Serotonin transporter gene deficiency is associated with sudden death of newborn mice through activation of TGF-beta1 signalling.
The serotonin transporter (SERT) gene has been proposed as a candidate gene responsible for the sudden infant death syndrome (SIDS). In this study, for the first time we obtained a SERT-knockout (KO) mouse model which reproduces SIDS phenotype. SERT-KO mice were generated by mating SERT(Cre/+) heterozygous mice. The SERT-KO mouse embryos at the pre-natal stage E18.5 were lacking of SERT mRNA and protein expression in the heart. A premature death of 75% of SERT-KO mice occurred in the first week after birth. LacZ staining of whole mounts and tissue sections of the heart from SERT(Cre/+);ROSA26R adult mice and E18.5 embryos demonstrated a marked localized expression of SERT in the right ventricle, the conal region, the vasculature, the atrial septum, the ventricular valves, and the sinoatrial node of the conduction system. These data suggest a cardiac phenotype for the sudden death of SERT-KO mice. Histological analysis of heart sections showed that SERT-KO mice develop cardiac fibrosis. Increased collagen accumulation in the myocardium and the valvular and perivascular regions, and enhanced expression of alpha-smooth muscle actin were detected in the heart of SERT-KO mice versus wild-type (WT) mice. Interestingly, higher expression levels of the 5-HT2A receptor and increased levels of phospho-SMAD2/3 and phospho-ERK1/2 were detected in SERT-KO mouse heart versus WT mice. Overall, our findings provide i) new insights into the role of SERT gene in SIDS, and ii) the first in vivo validation of the molecular mechanism involving the activation of TGF-beta1 signalling in the cardiac fibrosis.
Pavone
Luigi Michele
LM
Department of Biological Structures, Functions and Technologies, University of Naples Federico II, Via F. Delpino 1, 80137 Naples, Italy. pavone@dbbm.unina.it
Spina
Anna
A
Rea
Silviana
S
Santoro
Dionea
D
Mastellone
Vincenzo
V
Lombardi
Pietro
P
Avallone
Luigi
L
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D003645:Death, Sudden / Q000209:etiology*; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D044402:Receptor, Serotonin, 5-HT2A; D050486:Serotonin Plasma Membrane Transport Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3