Dorsal Signals in the Developing Telencephalon

发育中的端脑的背侧信号

• 批准号: 7017879
• 负责人: EDWIN S MONUKI
• 金额: $ 16.06万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7017879
• 关键词: DNA binding protein; Wnt gene /protein; biological signal transduction; bone morphogenetic proteins; brain interhemispheric activity; cell line; cerebral cortex; choroid plexus; developmental neurobiology; gene expression; genetically modified animals; laboratory mouse; mesencephalon; neurogenetics; neuropathology; prosencephalon; protein structure function; telencephalon

DESCRIPTION (provided by applicant): The bone morphogenetic proteins (Bmps) and Wnts represent two families of signaling proteins that are fundamental regulators of development. In the telencephalon - the forebrain subdivision that contains the cerebral cortex - multiple Bmps and Wnts are expressed in the dorsal midline region (DMR), where they are likely responsible for multiple developmental functions and malformation phenotypes. However, their presumed roles have remained elusive, due in part to significant functional redundancy among family members. This and other factors have greatly minimized the impact of traditional mouse genetics on elucidating Bmp and Wnt functions in telencephalic development. To overcome this limitation, we have adopted an alternative, but well established, genetic approach - lineage-specific cellular ablation. In our recently improved system, we utilize the restricted expression of a Bmp family member (Gdf7) to ablate a small subset of DMR cells in living mouse embryos. This causes marked reductions of multiple Bmp and Wnt signals, which are associated with three major defects in the telencephalon: 1) Loss of choroid plexus, the producer of cerebrospinal fluid, 2) selective cortical patterning defects, and 3) holoprosencephaly (HPE), the most common congenital malformation of the human brain. The central hypothesis driving this proposal is that DMR-dependent functions in telencephalic patterning and HPE pathogenesis are mediated by Bmp and Wnt signals. The immediate goal is to determine whether Bmp and Wnt signals are necessary and sufficient to mediate the embryonic patterning functions of the DMR. We will address this hypothesis by combining mouse genetics with explant cultures, which will be analyzed with markers and quantitative gene expression studies. K02 career development activities focus on developing a comprehensive explant approach and new DMR ablation models that allow for postnatal survival. Other personnel will consult and provide relevance to human HPE. These activities should facilitate the candidate's long-term goal of developing a research program that answers fundamental questions in early telencephalic development and disease. The insights into human HPE provide immediate relevance to public health. In addition, this project should lay the groundwork for understanding other human brain disorders that involve Bmp and Wnt signals.

描述（由申请人提供）：骨形态发生蛋白（BMP）和WNT代表两个信号蛋白的家族，这些家族是发展的基本调节剂。在尾脑 - 包含大脑皮层的前脑细分 - 多个BMP和WNT在背部中线区域（DMR）中表达，在那里它们可能负责多个发育功能和畸形表型。但是，他们假定的角色仍然难以捉摸，部分原因是家庭成员的功能冗余。这个和其他因素极大地降低了传统小鼠遗传学对阐明BMP和WNT功能在脑脑发育中的影响。为了克服这一限制，我们采用了一种替代但良好的遗传方法 - 谱系特异性细胞消融。在我们最近改进的系统中，我们利用BMP家族成员（GDF7）的受限表达在活小鼠胚胎中消除了一小部分DMR细胞。这会导致多个BMP和WNT信号的显着减少，这些信号与尾脑中的三个主要缺陷有关：1）脉络膜丛的损失，脑脊液的生产国，2）选择性皮质模式缺陷，3）最常见的先天性脑畸形，是人类最常见的人类大脑。推动该提议的中心假设是远程脑图案和HPE发病机理中依赖于DMR的功能是由BMP和WNT信号介导的。直接目标是确定BMP和Wnt信号是否需要且足以介导DMR的胚胎模式函数。我们将通过将小鼠遗传学与外植体培养物相结合来解决这一假设，该培养物将通过标记和定量基因表达研究进行分析。 K02职业发展活动致力于开发一种综合的外观方法和新的DMR消融模型，以实现产后生存。其他人员将咨询并提供与人类HPE的相关性。这些活动应促进候选人的长期目标，即制定一项研究计划，以回答早期脑脑发育和疾病中的基本问题。对人类HPE的见解提供了与公共卫生的直接相关性。此外，该项目应该为理解涉及BMP和WNT信号的其他人脑疾病奠定基础。