Dorsal Signals in the Developing Telencephalon

描述(申请人提供)：骨形态发生蛋白(BMPS)和WNTS代表两个信号蛋白家族，它们是发育的基本调节因子。在端脑--包含大脑皮层的前脑区--多个BMP和WNT在背中线区域(DMR)表达，它们可能与多种发育功能和畸形表型有关。然而，他们推定的角色仍然难以捉摸，部分原因是家庭成员之间的大量职能冗余。这一因素和其他因素极大地降低了传统小鼠遗传学在阐明BMP和Wnt在端脑发育中的功能方面的影响。为了克服这一局限性，我们采用了另一种成熟的遗传方法--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)的限制表达来去除活着的小鼠胚胎中的一小部分DMR细胞。这会导致多个BMP和WNT信号显著减少，这与端脑的三个主要缺陷有关：1)脉络丛丢失，产生脑脊液；2)选择性皮质模式缺陷；3)全前脑畸形(HPE)，人类大脑最常见的先天性畸形。支持这一建议的中心假设是，DMR在端脑模式和HPE发病机制中的依赖功能是由BMP和Wnt信号介导的。目前的目标是确定BMP和Wnt信号是否是必要的和充分的，以介导DMR的胚胎构型功能。我们将通过将小鼠遗传学与外植体培养相结合来解决这一假设，这将通过标记和定量基因表达研究进行分析。K02职业发展活动的重点是开发一种全面的外植体方法和新的DMR消融模式，以允许出生后存活。其他人员将咨询并提供与人类HPE相关的信息。这些活动应该有助于候选人的长期目标，即开发一个研究计划，回答早期端脑发育和疾病的基本问题。对人类HPE的洞察提供了与公共卫生直接相关的信息。此外，这个项目应该为理解涉及BMP和WNT信号的其他人类大脑疾病奠定基础。

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.