Mesenchymal-neuroepithelial interactions in the developing telencephalon.

大脑皮层是人类智力的基础。据信，其规模的增加， 神经元的旋转和扩张，介导了智力的增长， 哺乳动物进化种属特异性皮层细胞结构在很大程度上是在胚胎发生过程中确定的， 集成了小区自治和非自治机制。我们才刚刚开始了解 调节皮质大小和脑回化的机制，以及特定分泌分子对脑回化的贡献。 这些皮质特征的发展尤其未被充分研究。在发育过程中，大脑 皮质位于端脑背侧中线的外侧。几个信号中心 在发育中的端脑中有描述，包括间充质衍生物脑膜和 端脑背中线，分为脉络丛（ChP）和皮质缘（CH）。除了 分泌信号分子，ChP还产生脑脊液，使大脑恢复和保护大脑， 而CH是背侧脑的主要生发区。在分析转录因子的作用时， Lmx 1a和Lmx 1 B的突变体中，我们发现Lmx 1 a/B双突变体，而不是单突变体，具有一种特殊的表型， 受损的端脑背中线，以及扩张但分层的新皮质，局部过度生长 类似于脑回，并且上层神经元的数量增加。此外，在Lmx 1 a/B双突变体中， 背中线谱系与更多外侧神经上皮的分离严重受损， 背中线祖细胞异常分散到更外侧的神经上皮，包括新皮质。到 令人惊讶的是，我们发现Lmx 1a和1b从未在新皮层中表达，也没有在大脑皮层中共同表达。 端脑相反，在发育过程中，Lmx 1a表达仅限于ChP和CH，而Lmx 1b表达仅限于ChP和CH。 在邻近的头部间充质中表达，这表明以前未被认识到的间充质背侧 中线相互作用调节端脑发育的关键方面。本提案的目的是 定义Lmx 1 a/B依赖性间充质/神经上皮途径，调节 端脑背中线和新皮质。在目标1中，我们将定义Lmx 1a和1b如何调节 端脑背中线图案化和CH生长，这两个知之甚少的过程，这是至关重要的 在目标2中，我们将确定背中线信号传导的新作用， 新皮层的回旋和上层神经元的扩张，并定义背中线分泌分子 调解这些过程。在目标3中，我们将定义一个Lmx 1a/b依赖的分子途径， 分离的背中线谱系从更多的侧面神经上皮，并表明这一进程是 这对在小鼠中获得适当的皮质大小至关重要。我们的研究将确定新的基本机制 调节端脑发育，并可能提供新的见解皮质进化和人类 大脑发育障碍

The cerebral cortex is the substrate of human mental prowess. It is believed that its increase in size, with gyrification and expansion of upper layer neurons, mediates the growth of intellectual capacity during mammalian evolution. Species-specific cortical cytoarchitecture is largely determined during embryogenesis, integrating both cell autonomous and non-autonomous mechanisms. We are just beginning to understand the mechanisms regulating cortical size and gyrification, with contribution of specific secreted molecules into development of these cortical characteristics being particularly understudied. During development, the cerebral cortex arises in the telencephalon, lateral to the telencephalic dorsal midline. Several signaling centers have been described in the developing telencephalon, including a mesenchymal derivative meninges and the telencephalic dorsal midline, subdivided into the choroid plexus (ChP) and cortical hem (CH). In addition to secreting signaling molecules, the ChP also produces cerebrospinal fluid that nourishes and protects the brain, while the CH is a major germinal zone in dorsal brain. While analyzing the role of the transcription factors Lmx1a and Lmx1b, we found that Lmx1a/b double, but not single, mutants have an extraordinary phenotype of a compromised telencephalic dorsal midline, and expanded, yet layered neocortex with local overgrowths resembling gyri and an increased number of upper layer neurons. In addition, in Lmx1a/b double mutants, the segregation of the dorsal midline lineage from more lateral neuroepithelium was severely compromised, with dorsal midline progenitors aberrantly dispersing into more lateral neuroepithelium, including the neocortex. To our surprise, we found that Lmx1a and 1b are never expressed in the neocortex nor coexpressed in the telencephalon. Instead, during development, Lmx1a expression is limited to the ChP and CH while Lmx1b is expressed in the adjacent head mesenchyme, suggesting that previously unrecognized mesenchymal-dorsal midline interactions regulate key aspects of the telencephalic development. The goal of this proposal is to define Lmx1a/b - dependent mesenchymal / neuroepithelial pathways regulating development of the telencephalic dorsal midline and neocortex. In Aim 1 we will define how Lmx1a and 1b regulate the telencephalic dorsal midline patterning and CH growth, two poorly understood processes, which are critical for proper formation of the ChP and CH. In Aim 2 we will identify a new role of dorsal midline signaling in neocortical gyrification and expansion of upper layer neurons, and define dorsal midline secreted molecules mediating these processes. In Aim 3 we will define an Lmx1a/b-dependent molecular pathway regulating the segregation of the dorsal midline lineage from more lateral neuroepithelium and show that this process is critical to achieve proper cortical size in mice. Our studies will identify novel fundamental mechanisms regulating telencephalic development and are likely to provide new insights into cortical evolution and human developmental brain disorders.