Genetic Analysis of Forebrain Patterning & Neurogenesis

描述（由申请人提供）：我们的大脑半球是我们用于我们的最高智力功能。当它们在发育过程中不能正常形成时，就会发生破坏性的疾病。最常见的前脑发育缺陷是前脑无裂畸形，其中两个半球未能分开。尽管大脑半球发育对正常脑功能的重要性，但人们对将简单的胚胎神经前体细胞转化为结构复杂的成人大脑半球的机制知之甚少。本研究的目的是了解两个家族的分泌信号因子，骨形成蛋白和FGF，在大脑半球的早期发育中的功能。具体来说，目的是确定这些因素是否需要在体内诱导半球的形成，图案的侧和腹侧区域，形成中线，分开他们，并调节彼此的活动以及活动的另一个因素在中线形成，SHH必不可少。在小鼠中，FGF和BMP在体内这些过程中的作用的直接遗传测试以前是困难的，因为这些因子在神经发育开始之前也在胚胎中发挥重要作用。为了解决这个问题，使用条件遗传方法，其中多个BMP和FGF受体基因在胚胎大脑半球中被特异性删除，而不影响它们在胚胎其余部分的功能。在人类和小鼠中，SHH基因的突变会导致大脑中线的缺失，从而导致前脑无裂畸形。一个仍然没有答案的问题是，在大脑半球腹侧表达的SHH是如何形成腹侧中线和背侧中线的。初步证据表明，FGF和BMP是必不可少的腹侧，吻侧和背侧中线结构的形成和FGF的下游SHH在这个过程中的作用。该证据表明，SHH通过FGF和BMP信号传导在从腹侧到背侧中线的信号级联中起作用，并提供了人类和小鼠中SHH导致前脑无裂畸形的机制。

DESCRIPTION (provided by applicant): Our cerebral hemispheres are what we use for our highest intellectual functions. When they do not form normally during development, devastating disorders ensue. The most common developmental forebrain defect is holoprosencephaly, in which the hemispheres fail to separate. Despite the importance of cerebral hemisphere development to normal brain function, little is known about the mechanisms that transform a simple sheet of embryonic neural precursor cells into the structurally complex adult cerebral hemispheres. The goal of this study is to understand how two families of secreted signaling factors, the BMPs and FGFs, function in early development of the hemispheres. Specifically, the aims are to determine if these factors are required in vivo to induce the formation of the hemispheres, to pattern their lateral and ventral areas, to form the midline that separates them, and to regulate each others activity as well as the activity of another factor essential in midline formation, SHH. In mice, a direct genetic test of the role of FGFs and BMPs in these processes in vivo has previously been difficult because these facotrs also play essential roles in the embryo prior to the onset of neural development. To get around this problem, a conditional genetic approach is used whereby multiple BMP and FGF receptor genes are deleted specifically in the embryonic cerebral hemispheres without affecting their function in the rest of the embryo. In both humans and mice, mutations in the SHH gene cause a loss of the cerebral midline, and hence holoprosencephaly. A question that remains unanswered is how SHH, which is expressed on the ventral side of the hemispheres, is required for forming not only the ventral midline, but also the dorsal midline. Preliminary evidence indicates that FGFs and BMPs are essential in forming ventral, rostral, and dorsal midline structures and that FGFs act downstream of SHH in this process. This evidence suggests that SHH acts in a signaling cascade operating from ventral to dorsal midline through FGF and BMP signaling and provides a mechanism by which SHH in humans and mice leads to holoprosencephaly.