Role of Math1 in brain stem & cerebellar development

Math1 在脑干中的作用

• 批准号: 6887091
• 负责人: Matthew F Rose
• 金额: $ 3.15万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2007-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6887091
• 关键词: brain stem; cell differentiation; cell proliferation; cell type; central nervous system; cerebellum; cytogenetics; developmental genetics; developmental neurobiology; gene expression; gene mutation; genetic mapping; genetically modified animals; histology; laboratory mouse; predoctoral investigator; transcription factor

DESCRIPTION (provided by applicant): The mouse atonal homolog 1 (Math1) encodes a basic helix-loop-helix transcription factor that is expressed in the progenitors of the inner ear hair cells, cerebellar granule cells, spinal cord dorsal interneurons, several brain stem nuclei, merkel cells, and the secretory cells of the intestine. Of note also is that the expression of Math1 and HATH1 is upregulated in medulloblastomas from mouse models and human samples, respectively. Gene targeting has demonstrated that Math1 is necessary for the genesis of many of these cells. However, some of these cell populations differentiate postnatally, and because Math1 null mice die at birth from an inability to breathe, the fate of these cells and their dependence on Math1 function have not been fully analyzed. To study the fate of all Math1-expressing cells, we have targeted an inducible Cre recombinase to the Math1 genomic locus. When these mice are crossed to a reporter strain, this Cre/loxP system will permanently label Math1-expressing cells such that their entire downstream lineage can be traced into adulthood. We will also use an existing conditional allele to delete Math1 in the brainstem and cerebellum at specific embryonic and postnatal time points in order to identify the brainstem nucleus required for the respiratory defect in the Math1 nulls and to study the role of Math1 in cerebellar granule cell proliferation and differentiation. The combination of these fate-mapping and conditional knock-out studies should provide basic knowledge about the development of Math1-expressing cell types, the initiation of breathing, and the connection between neuronal progenitor proliferation and differentiation. This information may provide insight into hindbrain diseases such as Medulloblastomas, and perinatal respiratory dysfunction such as Sudden Infant Death Syndrome.

描述（由申请人提供）：小鼠无性同源物1 （Math1）编码一种基本的螺旋-环-螺旋转录因子，该转录因子在内耳毛细胞、小脑颗粒细胞、脊髓背侧中间神经元、几种脑干核、默克尔细胞和肠分泌细胞的祖细胞中表达。同样值得注意的是，Math1和HATH1的表达分别在小鼠模型和人类样本的成神经管细胞瘤中上调。基因靶向已经证明，Math1对于许多这些细胞的发生是必要的。然而，这些细胞群中的一些在出生后分化，并且由于Math1缺失小鼠在出生时因无法呼吸而死亡，因此这些细胞的命运及其对Math1功能的依赖尚未得到充分分析。为了研究所有表达Math1的细胞的命运，我们将一个可诱导的Cre重组酶靶向到Math1基因组位点。当这些小鼠与报告菌株杂交时，Cre/loxP系统将永久标记表达math1的细胞，这样它们的整个下游谱系可以追溯到成年期。我们还将使用现有的条件等位基因在特定的胚胎和出生后时间点删除脑干和小脑中的Math1，以确定Math1空区呼吸缺陷所需的脑干核，并研究Math1在小脑颗粒细胞增殖和分化中的作用。这些命运定位和条件敲除研究的结合应该提供关于math1表达细胞类型的发展、呼吸的开始以及神经元祖细胞增殖和分化之间的联系的基本知识。这一信息可能为后脑疾病（如髓母细胞瘤）和围产期呼吸功能障碍（如婴儿猝死综合征）提供深入了解。