The role of Netrin-DCC in the development of the corpus callosum

在胚胎发育期间，神经元发出轴突，连接到大脑中的其他目标神经元。这些轴突的正确连接对大脑功能至关重要。大脑中最大的轴突束称为胼胝体，连接左右大脑半球的神经元。当胼胝体没有形成时，患者会出现明显的认知、运动和感觉缺陷。这种情况被称为胼胝体发育不全（ACC），与50多种不同的人类先天性综合征有关。因此，了解如何参与胼胝体功能的形成在正常发展的基因和分子可以为我们理解什么是错的ACC. In这个建议中，我们将探讨轴突导向分子Netrin 1的作用，及其受体DCC，在胼胝体发育的小鼠模型和人类胼胝体畸形的基础。虽然Netrin 1-DCC信号传导传统上与轴突引导机制相关，但我们假设这些分子可能在细胞粘附中发挥不同的作用，并最终在两个大脑半球的融合中发挥作用，以允许胼胝体形成的方式。Netrin 1-DCC信号的第二个作用可能是在中线正确融合后指导这些轴突，我们在提案的目标2中对此进行了研究。最后，我们正在与加州大学旧金山分校的儿科神经学家合作，他已经确定了ACC患者DCC基因的几个突变。在目标3中，我们测试这些突变是否会破坏DCC在胼胝体轴突寻路中的功能。了解这些基因在大脑发育过程中的功能以及它们的功能在ACC中如何改变，对于为这些患者提供正确的诊断和预后至关重要。最终，更多地了解这些基因的功能也可以预防这些疾病。

During embryonic development neurons send out axons that connect to other target neurons within the brain. The proper connectivity of these axons is vital to brain function. The largest axon tract in the brain is called the corpus callosum and connects neurons in the left and right cerebral hemispheres. When the corpus callosum does not form, significant cognitive, motor and sensory deficits occur in patients. This condition, known as agenesis of the corpus callosum (ACC), is associated with over 50 different human congenital syndromes. Thus understanding how the genes and molecules involved in the formation of the corpus callosum function in normal development can provide the basis for our understanding of what goes wrong in ACC. In this proposal we will investigate the role of the axon guidance molecule Netrin1, and its receptor DCC, in development of the corpus callosum in both a mouse model and in humans with malformations of the corpus callosum. Although Netrin1-DCC signalling has traditionally been associated with mechanisms of axon guidance, we hypothesize that these molecules may play a different role, specifically in cellular adhesion and ultimately in the fusion of the two cerebral hemispheres, in a manner that allows the corpus callosum to form. A second role for Netrin1-DCC signalling may be in the guidance of these axons once the midline has fused correctly and we investigate this in Aim 2 of the proposal. Finally, we are collaborating with a paediatric neurologist at UCSF, who has identified several mutations in the DCC gene in patients with ACC. In Aim 3 we test whether these mutations disrupt the function of DCC in callosal axon pathfinding. Understanding how these genes function during development of the brain and how their function may be altered in ACC is crucial to providing a proper diagnosis and prognosis for these patients. Ultimately, understanding more about how these genes function could also lead to prevention of these disorders.