The embryological and molecular basis of Zic2 involvement in holoprosencephaly

大脑是人体中最复杂的器官，大脑的疾病或紊乱可能在生命的任何阶段变得明显。一般来说，这些问题对受影响的个人及其家庭有深远的影响。在出生时或在生命的最初几年内明显的大脑发育的最常见问题之一被称为前脑无裂畸形（HPE）。这种情况会影响大脑和面部的中线，并可能导致智力，运动和语言发育延迟，癫痫发作和明显的面部异常。在最严重的形式，只有一只眼睛在脸的中间发展，这种情况被称为独眼症，大多数严重受影响的儿童将在妊娠后期或出生时死亡。这种情况可以遗传，但由于导致这种问题的遗传病变影响不同的人，人们可以携带致病的遗传变化（S）而不知道它。我们需要识别和研究导致这种情况的遗传病变，以便开始了解我们如何可以阻止这些突变影响发育中的胎儿。因为研究人类胚胎发育很困难，我们已经建立了这种情况的小鼠模型。在小鼠模型中，只有一个基因（称为Zic 2）被改变，具有两个这种改变的胚胎会发展出最严重的独眼畸形，并在妊娠的后半期死亡。这意味着该基因的正常作用是阻止我们发展HPE。我们将使用这种小鼠模型来观察Zic2基因何时以及如何预防HPE。此外，我们将通过将携带Zic 2突变的小鼠与携带第二个基因突变的小鼠进行繁殖，以观察Zic 2与其他基因的相互作用，该突变也可能导致HPE。这些实验非常重要，因为如果我们了解Zic 2和其他基因如何保护我们免受HPE的侵害，我们就可以开始设计策略来降低儿童患这种疾病的风险。

The brain is the most complex organ in the human body and diseases or disorders of the brain can become evident at any stage of life. Generally such problems have profound consequnces for the affected individuals and their families. One of the most common problems of brain development that is evident either at birth or within the first years of life is called holoprosencephaly (HPE). This condition affects the midline of the brain and the face and can lead to delay in mental, motor and language development, seizures, and obvious facial abnormalities. In its most severe form only one eye develops in the middle of the face, a condition known as cyclopia and a large majority of the severely affected children will die late in gestation or at birth. This condition can be inherited, but because the genetic lesions that cause this problem affect different people differently, people can carry the causative genetic change(s) without knowing it. We need to identify and study the genetic lesions that contribute to this condition in order to begin to understand how we can stop these mutations affecting the developing foetus. Because it is difficult to study embryonic development in humans we have generated a mouse model of this condition. In the mouse model just one gene (called Zic2) is altered and embryos that have two copies of this alteration develop the most severe form of cyclopia and die in the second half of gestation. This means that the normal role of this gene is to stop us developing HPE. We will use this mouse model to see just when and how the Zic2 gene prevents HPE. In addition, we will look to see what other genes Zic2 interacts with by breeding mice that carry the mutation in Zic2 with mice that carry a mutation in a second gene that can also cause HPE. These experiments are very important because if we understand how Zic2 and other genes protect us from HPE we can begin to design strategies to decrease the risk of a child developing this condition.