Genetic analysis of forebrain patterning and neurogenesis

前脑模式和神经发生的遗传分析

基本信息

批准号：
9267534
负责人：
JEAN M HEBERT
金额：
$ 41.75万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-15 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9267534
关键词：
Adopted Affect Alpha Cell Binding Binding Sites Biochemical Brain Brain Diseases Cell Culture Techniques Cell Death Cell Survival Cell surface Cells Complex Cultured Cells Data Development Developmental Process Disease Elements FOXG1B gene 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 experimental study extracellular genetic analysis in vivo migration mutant neurogenesis precursor cell promoter public health relevance regenerative response stem stemness

项目摘要

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）对于大量发育过程（包括大脑发育的许多方面）至关重要。 FGF如何在一种情况下诱导细胞命运，并在另一个情况下促进增殖，迁移，分化或生存是未知的。一种可能性是不同的细胞内信号转导途径在不同细胞中被FGF激活。几乎完全基于生化和细胞培养数据，已经提出了FGF受体激活的几种细胞内传感器。其中最被接受的是FGF受体底物（FRS）蛋白，其中有两个家庭成员。但是，在体内任何FGF信号传导是否需要FRS仍然未知。令人惊讶的是，我们的初步数据表明，在早期脑脑发育中FGF信号的某些方面仅需要FRS。因此，在AIM 1中，我们研究了FRS在尾脑发育过程中在体内传输FGF信号中的作用。我们专注于以前显示的端脑发育的两个过程需要FGF。通过用三重FGF受体敲除消除FGF信号传导，我们发现FGF对于端脑细胞存活而言是必不可少的，后来又抑制了皮质前体中茎向祖细胞到祖细胞过渡。在每种情况下，我们将确定FGF信号是否取决于FRS。关于细胞为什么对FGF响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相互作用以调节早期端脑中的细胞存活和CDKN1A转录。这些发现提供了一个体内上下文，以破译细胞在决定采用命运之前如何整合多个信号。在AIM 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，FOXG1的表达是由FGF促进的，可以抑制SMAD复合物与培养细胞中CDKN1A启动子的结合。在AIM 3中，我们确定FOXG1是否参与体内早期端脑细胞中的CDKN1A转录，以及FOXG1，SMAD4和CDKN1A是否可以基因相互作用。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The genetics of early telencephalon patterning: some assembly required.

DOI：
10.1038/nrn2463
发表时间：
2008-09
期刊：
Nature reviews. Neuroscience
影响因子：
0
作者：
Hébert JM;Fishell G
通讯作者：
Fishell G

The transition from radial glial to intermediate progenitor cell is inhibited by FGF signaling during corticogenesis.

DOI：
10.1523/jneurosci.3844-09.2009
发表时间：
2009-11-18
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Kang W;Wong LC;Shi SH;Hébert JM
通讯作者：
Hébert JM

L1cam curbs the differentiation of adult-born hippocampal neurons.