The genomics of labour : global gene expression profiling and oxytocin receptor gene expression

Résumé fourni par la source

Premature labour and subsequent premature birth is a leading cause of neonatal morbidity and mortality. We studied marine labour at term and preterm with models of intrauterine infection and ovariectomy using Affymetrix microarray U74Av2 (containing 12,488 probe sets) and real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) to identify novel candidate genes involved in normal and preterm labour. Strict statistical analysis revealed 320, 188, and 74 genes to be significantly induced or suppressed during normal, infection-induced, and ovariectomy-induced labour, respectively. Novel genes identified include: associated with normal labour: alpha fetoprotein, apolipoprotein A1, fibrinogen polypeptides, cytochrome P45011a, Purkinje cell protein 4 (PCP4), and chloride channel calcium activated 3; associated with infection: numerous inflammatory mediators, alpha fetoprotein, apolipoprotein Al, and fibrinogen polypeptides. Small proline-rich protein 2 family genes were induced by ovariectomy and infection. PCP4 gene was induced after ovariectomy, but suppressed at normal labour. Only seven genes were significantly regulated (each induced) at labour in all models implying that unique gene networks are involved in normal and preterm labour induced by various stimuli. These included genes for plasminogen activator inhibitor 1 and for contraction associated proteins (CAPS) required for uterine activation and uterotonin stimulation of contractions. The oxytocin receptor (OTR) gene encodes one such CAP. Northern blot and real-time RT-PCR demonstrated its up-regulation prior to labour in each model, preferentially in normal labour. Uterine contraction promotes increased central and peripheral oxytocin release and synaptic plasticity. To further examine the role of the OTR, we developed an OTR-lacZ reporter mouse. We mapped, by X-gal histochemistry, the distribution of OTR gene expression in the early postparturient mouse brain and identified novel regions of expression. These included the piriform cortex, entorhinal cortices, and parasubiculum, which support memory function. Dorsal tegmental, vestibular, and lateral reticular nuclei expression suggests the transmission of locomotor inputs. Hypoglossal, facial, and spinal trigeminal nuclei support maternal behaviours. We also more accurately demarcated OTR gene expression in the solitary tract nucleus responsible for relaying contraction stimulation of oxytocin release. These studies provide a more accurate knowledge base for the development of successful therapies to decrease the incidence of premature labour.

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