Regulation of cortical development by Nfi genes.

大脑两个半球的神经元通过一个叫做胼胝体的大纤维束相互连接。在超过50种不同的人类先天性综合征中，胼胝体不能正常形成。这类综合征，包括阿卡迪综合征、安德曼综合征、夏皮罗综合征和肢端胼胝体综合征，可导致儿童智力迟钝、癫痫发作、缺乏运动协调和眼部异常。我们关于小鼠和人类大脑发育的数据表明，小鼠是一个很好的模型系统，可以用来理解大脑在发育过程中是如何连接起来的，以及在这些疾病中可能出现的问题。在这里，我们研究了一个名为核因子1（Nfi）基因家族在大脑发育中的作用。当在小鼠中发生突变时，该基因家族的成员，主要是Nfia和Nfib，会导致大脑严重畸形。表型包括不能形成一些中线胶质细胞群，扣带回皮质扩张和胼胝体丢失。中线胶质细胞群和扣带回皮质的适当形成对于胼胝体的形成和正确的脑布线是必不可少的。在发育过程中，扣带皮层中的大脑线路缺陷可能是精神分裂症、双相情感障碍和抑郁症等疾病的基础。在这个项目中，我们将讨论Nfi基因控制大脑发育的功能机制。这项研究的预期成果是确定新的机制和遗传途径，这些机制和遗传途径对大脑两侧之间形成连接和扣带皮层的正确形成至关重要。这些结果将提高我们对大脑如何形成以及在发育过程中可能导致儿童和成人神经和认知缺陷的机制的理解。

Neurons in the two hemispheres of the brain make connections with each other via a large fibre tract called the corpus callosum. In over fifty different human congenital syndromes the corpus callosum fails to form properly. Such syndromes, which include Aicardi syndrome, Andermann syndrome, Shapiro syndrome and Acrocallosal syndrome, can result in mental retardation, seizures, lack of motor coordination and ocular abnormalities in children. Our data on both mouse and human brain development show that the mouse is an excellent model system for understanding how the brain becomes wired up during development and what may go wrong in these disorders. Here we investigate the role of a family of genes called nuclear factor one (Nfi) genes in brain development. When mutated in mice, members of this gene family, principally Nfia and Nfib, cause severe malformations of the brain. The phenotype inlcudes a failure to form some midline glial populations, the expansion of the cingulate cortex and loss of the corpus callosum. The propoer formation of midline glial populations and the cingulate cortex are essential to callosal fomration and correct brain wiring. Defects in brain wiring in the cingulate cortex during development may underlie disorders such as schizophrenia, bipolar disorder and depression. In this project we will address the mechanism of function underlying the control of brain development by the Nfi genes. The expected outcomes of this research are to identify new mechanisms and genetic pathways critical to the formation of connections between the two sides of the brain and proper formation of the cingulate cortex. These results will improve our understanding of how the brain forms and what mechanisms may be disrupted during development that result in neurological and cognitive deficits in children and adults.