Genetic analysis of forebrain patterning and neurogenesis

前脑模式和神经发生的遗传分析

• 批准号: 8503139
• 负责人: JEAN M HEBERT
• 金额: $ 41.75万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8503139
• 关键词: Adopted; Affect; Binding; Binding Sites; Biochemical; Brain; Cell Culture Techniques; Cell Death; Cell Survival; Cell surface; Cells; Complex; Craniosynostosis; Cultured Cells; Data; Development; Developmental Process; Disease; Elements; Family; Family member; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Gene Expression; Genetic Transcription; Knock-out; Myelitis; Neurons; Pattern; Pharmacologic Substance; Phenotype; Process; Prosencephalon; Proteins; Receptor Activation; Role; Signal Transduction; Signal Transduction Pathway; Specific qualifier value; Spinocerebellar Ataxias; Stem cells; Telencephalon; Testing; Transcriptional Regulation; Transducers; base; cell type; extracellular; genetic analysis; in vivo; migration; mutant; neurogenesis; precursor cell; promoter; public health relevance; regenerative; research study; response; stem; stemness

DESCRIPTION (provided by applicant): Fibroblast Growth Factors (FGFs) are critical for a vast array of developmental processes, including many aspects of brain development. How FGFs induce cell fates in one context, and promote proliferation, migration, differentiation, or survival in another is unknown. One possibility is that different intracellular signal transduction pathways are activated by FGFs in different cells. Based almost exclusively on biochemical and cell culture data, several intracellular transducers of FGF receptor activation have been proposed. Most accepted among these are the FGF Receptor Substrate (FRS) proteins, of which there are two family members. However, whether FRS is required for any FGF signaling in vivo remains unknown. Surprisingly, our preliminary data indicate that FRS is only required for certain aspects of FGF signaling in early telencephalon development. Hence in Aim 1, we examine the role of FRS in transducing FGF signals in vivo during telencephalon development. We are focusing on two processes of telencephalon development that we have previously shown require FGFs. By abolishing FGF signaling with a triple FGF receptor knockout, we found that FGFs are essential early for telencephalic cell survival and later for inhibiting the stem to progenitor cell transition in cortical precursors. In each case, we will determine if FGF signaling depends on FRS. Another possible explanation for why cells respond differently to FGFs is that other extracellular factors modulate its effects. For example, we have found that FGFs, WNTs, and TGFbs interact to regulate cell survival and Cdkn1a transcription in the early telencephalon. These findings provide an in vivo context to decipher how a cell can integrate multiple signals before deciding to adopt a fate. In Aim 2, we examine how the transcriptional regulation of Cdkn1a by extracellular signals affects cell fate. Moreover, FOXG1, whose expression is promoted by FGFs, can inhibit the binding of a SMAD complex to the promoter of Cdkn1a in cultured cells. In Aim 3, we determine whether and how Foxg1 participates in regulating Cdkn1a transcription in early telencephalic cells in vivo and whether Foxg1, Smad4, and Cdkn1a genetically interact.

描述（由申请人提供）：成纤维细胞生长因子（FGF）对于一系列发育过程至关重要，包括大脑发育的许多方面。 FGF 如何在一种情况下诱导细胞命运，并在另一种情况下促进增殖、迁移、分化或存活尚不清楚。一种可能性是细胞内信号转导不同 途径由不同细胞中的 FGF 激活。几乎完全基于生化和细胞培养数据，已经提出了几种 FGF 受体激活的细胞内转导器。其中最被接受的是 FGF 受体底物 (FRS) 蛋白，其中有两个家族成员。然而，体内 FGF 信号传导是否需要 FRS 仍不清楚。令人惊讶的是，我们的初步数据表明，FRS 仅是早期端脑发育中 FGF 信号传导的某些方面所需要的。 因此，在目标 1 中，我们研究了 FRS 在端脑发育过程中体内转导 FGF 信号中的作用。我们正在关注端脑发育的两个过程，我们之前已经证明这两个过程需要 FGF。通过三重 FGF 受体敲除消除 FGF 信号传导，我们发现 FGF 对于端脑细胞早期存活以及随后抑制皮质前体中干细胞向祖细胞的转变至关重要。在每种情况下，我们都会确定 FGF 信号传导是否 取决于 FRS。 细胞对 FGF 反应不同的另一个可能的解释是其他细胞外因子调节其作用。例如，我们发现 FGF、WNT 和 TGFb 相互作用来调节早期端脑的细胞存活和 Cdkn1a 转录。这些发现提供了一个体内背景，以破译细胞在决定采用命运之前如何整合多个信号。在目标 2 中，我们研究了细胞外信号对 Cdkn1a 的转录调控如何影响细胞命运。此外，FGFs促进表达的FOXG1可以抑制培养细胞中SMAD复合物与Cdkn1a启动子的结合。在目标 3 中，我们确定 Foxg1 是否以及如何参与调节体内早期端脑细胞中的 Cdkn1a 转录，以及 Foxg1、Smad4 和 Cdkn1a 是否存在遗传相互作用。