Determination of neuronal fates in visual cortex

描述(申请人提供)：在发育过程中，前体细胞产生大量不同的年轻神经元，这些神经元从它们的起始点迁移出来，并建立不同的身份，包括形成特定的连接。本研究的主要目的是了解哺乳动物视皮层中的年轻神经元在发育过程中实现其成年身份、迁移到适当的位置以及与适当的靶细胞形成轴突连接的细胞和分子过程。由于皮层神经元迁移和连接的缺陷与癫痫、阅读障碍、精神分裂症、双相情感疾病和自闭症等多种疾病相关，皮质回路的形成和细化缺陷对视觉、认知和心理健康具有重要意义。我们研究的目标是确定调节视觉皮质神经发生的基因，并了解它们如何影响皮质回路的形成。我们将探讨以下具体问题：(1)Satb2是一种DNA结合蛋白，它调节染色质的组织，并在膝状体投射神经元中表达。为了探讨Satb2在命运决定中的作用，将分析Satb2条件突变小鼠的轴突投射、电生理特性和基因表达模式。(2)我们将鉴定和鉴定Satb2的下游效应因子，以及它们在调节膝状体投射神经元的层叠和轴突投射中的作用。(3)我们先前发现转录因子Fezf2和Ctip2调节皮质下投射神经元的识别，并且Fezf2、Ctip2和Satb2在基因上相互作用形成两条相互抑制的通路。我们将通过探索Fezf2/Ctip2和Satb2通路之间的遗传相互作用，来探索神经元如何决定皮质下投射和胼胝体下投射神经元的命运。(4)我们将使用移植的方法来探索获得皮质下投射神经元与胼胝体投射神经元的身份。通过将假定的第6层细胞移植到第2/3层，反之亦然，我们将确定年轻的皮质神经元是否以及在多长时间内可以对局部命运诱导线索做出反应，并改变其正常的层特异性身份，如其树突形态、局部和长距离轴突投射以及层特异性基因表达模式。 公共卫生相关性：皮质回路的形成和形成的缺陷对视觉、认知和精神健康具有基本的影响，因为皮质神经元的迁移和连接缺陷与包括癫痫、诵读困难、精神分裂症、双相情感疾病和自闭症在内的各种疾病有关。我们研究的目标是确定调节视觉皮质神经发生的基因，并了解它们如何影响皮质回路的形成。

DESCRIPTION (provided by applicant): During development, progenitor cells produce a large diversity of young neurons that migrate away from their site of origin and establish distinct identities, including the formation of specific connections. The major aim of this research is to understand the cellular and molecular processes by which young neurons in the mammalian visual cortex achieve their adult identities during development, migrate to appropriate positions, and form axonal connections with appropriate target cells. Defects in the formation and elaboration of cortical circuits have fundamental implications for vision, cognition, and mental health, since defects in the migration and connectivity of cortical neurons are associated with a variety of disorders including epilepsy, dyslexia, schizophrenia, bipolar affective illness, and autism. The goals of our research are to identify the genes that regulate neurogenesis in the visual cortex and to understand how they affect the formation of cortical circuitry. We will explore the following specific issues: (1) Satb2 is a DNA-binding protein that regulates chromatin organization and is expressed in callosal projection neurons. To explore the role of Satb2 in fate determination, will analyze the axonal projections, electrophysiological properties, and gene expression patterns of neurons in mice with a conditional mutation of Satb2. (2) We will identify and characterize the downstream effectors of Satb2 and their roles in regulating the lamination and axonal projections of callosal projection neurons. (3) We found previously that the transcription factors Fezf2 and Ctip2 regulate the identity of subcortical projection neurons, and that Fezf2, Ctip2 and Satb2 interact genetically to form two mutually repressive pathways. We will explore how neurons decide between a subcortical vs. callosal projection neuron fate by exploring the genetic interactions between the Fezf2/Ctip2 and Satb2 pathways. (4) We will use transplantation methods to explore the acquisition of a subcortical vs. callosal projection neuron identity. By transplanting presumptive layer 6 cells into layer 2/3, and vice versa, we will ascertain whether and over what period of time a young cortical neuron can respond to local fate- inducing cues and alter its normal layer-specific identity, as assessed by its dendritic morphology, local and long distance axonal projections, and pattern of layer-specific gene expression. PUBLIC HEALTH RELEVANCE: Defects in the formation and elaboration of cortical circuits have fundamental implications for vision, cognition, and mental health, since defects in the migration and connectivity of cortical neurons are associated with a variety of disorders including epilepsy, dyslexia, schizophrenia, bipolar affective illness, and autism. The goals of our research are to identify the genes that regulate neurogenesis in the visual cortex and to understand how they affect the formation of cortical circuitry.