Poly(A)-binding proteins highlight the importance of regulated mRNA translation and stability in determining a functional materno-fetal interface

构成我们细胞的蛋白质是由作为遗传蓝图的基因编码的。储存在基因中的信息被表达或解码，通过一个称为基因表达的多步骤过程来产生蛋白质，这一途径的关键步骤之一是信使核糖核酸的翻译。为了正常运作，细胞和生物体需要在正确的时间、地点和正确的数量制造蛋白质。因此，仔细调控信使核糖核酸的翻译是至关重要的，控制不当会导致多种疾病，包括癌症、代谢、神经和生殖疾病。聚(A)结合蛋白(PABP)1是包括信使核糖核酸翻译在内的基因表达途径中多个步骤的中央调节因子。哺乳动物包含五个属于PABP家族的基因，其中两个(PABP1和PABP4)在全身许多类型的细胞中产生。虽然PABP1已被广泛研究，但对PABP1或其他家庭成员在人类健康中的潜在作用知之甚少。然而，我们最近发现，PABP4的缺失严重降低了哺乳动物的生育力。这似乎是由于母亲的问题，导致怀孕后期胎儿死亡。有趣的是，我们发现活着的婴儿通常都很小，这表明胎儿在子宫内存在发育问题(宫内生长受限)。胎儿宫内发育不良使婴儿在成年后容易出现健康问题，包括心血管疾病、中风和II型糖尿病。这些重要的观察结果表明，我们有一个独特的机会来研究一系列妊娠并发症的潜在原因，包括死产、晚期流产和宫内发育受限。全世界每年发生近300万例晚期死产，其中英国的死亡率(每200人中有1人)比几乎所有其他高收入国家都高。研究表明，死产可能是由胎盘、脐带问题或感染引起的，尽管在许多情况下，这些问题产生的原因尚不清楚。此外，高达30%的死产没有明显的原因，这强调了在这一领域进行研究的必要性。我们的研究旨在通过对PABP4的功能和调控靶点进行详细分析，并进一步研究在没有PABP4的情况下无法正常运作的细胞过程，来阐明这些问题。重要的是，这将与人类生殖组织中PABP4的研究平行。综上所述，这项工作提供了一个独特的机会来理解导致死产和宫内发育不良的途径和机制。这是为遭受这种损失的夫妇提供答案的第一步，从长远来看，可能会发现怀孕失败的新预后标志，可能表明需要进行医疗干预。最终，它可能为怀孕前或怀孕期间的治疗干预提供途径。

The proteins that make up our cells are encoded by genes that serve as a genetic blueprint. The information stored in genes is expressed, or decoded, to produce proteins by a multi-step process known as gene expression, with one of the critical steps in this pathway being mRNA translation. In order to function properly, cells and organisms need to make proteins at the right time, place and in the correct amount. Thus it is critical that mRNA translation is carefully regulated, with improper control leading to a wide variety of diseases including cancer, metabolic, neurological and reproductive disorders.Poly(A)-binding protein (PABP) 1 is a central regulator of multiple steps in the gene expression pathway, including mRNA translation. Mammals contain five genes belonging to the PABP family, two of which (PABP1 and PABP4) are produced in many cell types throughout the body. Although PABP1 has been extensively studied, little is known about the potential roles of PABP1, or other family members, in human health. However, we have recently found that an absence of PABP4 severely reduces mammalian fertility. This appears to be due to problems with the mother which lead to fetal death during the later stages of pregnancy. Interestingly, we see that live births are frequently small suggesting growth problems whilst in the womb (intrauterine growth restriction). Poor intrauterine growth predisposes human babies to health problems in adulthood including cardiovascular disease, stroke and type II diabetes. These important observations suggest that we have a unique opportunity to study the underlying causes of a spectrum of pregnancy complications including stillbirth, late miscarriage and intrauterine growth restriction. Nearly 3 million third-trimester stillbirths occur worldwide each year, with the UK having a higher rate (1 in 200) than almost every other high-income country. Research has shown that stillbirth can be caused by problems with the placenta, the umbilical cord or by infections, although in many cases the reasons why these problems arose is not understood. Moreover, up to 30% of stillbirths have no obvious cause, emphasising the need for research in this area. Our research aims to shed light on these issues by performing a detailed analysis of the functions and regulatory targets of PABP4, of which little is presently known, and by further investigating the cellular processes that fail to function normally in the absence of PABP4. Importantly, this will be paralleled by an investigation of PABP4 in human reproductive tissues. Taken together this work presents a unique opportunity to understand the pathways and mechanisms that lead to stillbirth and poor intrauterine growth. This forms the first step towards providing answers to couples that suffer such loss, and in the longer term may identify novel prognostic markers for pregnancy failure that could indicate the need for medical intervention. Ultimately it may offer avenues for therapeutic intervention prior to or during pregnancy.