Development of the commissural plate and its role in forebrain commissure development

在发育过程中，大脑一个半球的神经元与另一个半球的神经元连接并交流。在两个半球之间的这种神经连接被称为连接，它是跨越大脑中线的大束轴突（神经线）。前脑有三个连接体：胼胝体、海马连接体和前连接体。大脑的这种连接对其正常运作至关重要。当这些连接没有形成时，大脑就不能以基本的方式整合和处理信息。超过50种不同的人类先天性疾病与一个或多个前脑连接的畸形有关。这一提议调查了一种假设，即一种称为联合板（CP）的中线结构调节了所有前脑联合的发育。20世纪之交，CP首次在许多不同物种的解剖学上被描述，1968年在人类身上被描述。然而，从那时起，没有关于CP的论文发表。本提案中的实验将使用现代神经解剖学技术，特别是磁共振成像，分子和小鼠诱变技术以及轴突引导分析来研究CP。我们将检验CP作为所有交联轴突中线交叉点的基本独特之处的假设。我们产生仅破坏背侧CP形成的小鼠突变体，然后确定是否发生背侧连接的后续发育。我们还对人类胎儿大脑进行分子表达和成像分析。我们的目标是提供对人类先天性疾病中导致中线脑畸形和前脑裂缝发育不全的发育事件的理解。了解这些疾病的基础将导致更准确的诊断，并有可能通过遗传咨询进行预防。

During development, neurons in one hemisphere of the brain connect and communicate with neurons in the opposite hemisphere. Such neural connections between the two hemispheres are called commissures, which are large bundles of axons (neural-wires) that cross the midline of the brain. There are three commissures in the forebrain: the corpus callosum, the hippocampal commissure and the anterior commissure. This wiring of the brain is essential to its proper function. When these connections don't form, the brain cannot integrate and process information in fundamental ways. Over 50 different human congenital disorders are associated with the malformation of one or more of these forebrain commissures. This proposal investigates the hypothesis that a midline structure, called the commissural plate (CP), regulates the development of all forebrain commissures. The CP was first described anatomically at the turn of the 20th century in a number of different species, and in humans in 1968. However, since this time, no papers have been published on the CP. Experiments in this proposal will use modern neuroanatomical techniques, particularly magnetic resonance imaging, molecular and mouse mutagenesis techniques, and axon guidance assays, to study the CP. We will test the hypothesis that there is something fundamentally unique about the CP as the midline crossing point for all commissural axons. We generate mouse mutants that disrupt only dorsal CP formation and then determine whether the subsequent development of the dorsal commissures occurs. We also perform molecular expression, and imaging analyses on human foetal brains. Our goal is to provide an understanding of what developmental events are disrupted in human congential disorders resulting in midline brain malformations and agenesis of the forebrain commissures. Understanding the basis of these disorders will lead to more accurate diagnoses and potentially their prevention through genetic counseling.