Role of Math1 in brain stem & cerebellar development

Math1 在脑干中的作用

• 批准号: 6963377
• 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 2007-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6963377
• 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atonal同源物1（MATH1）编码一种基本的螺旋 - 环螺旋转录因子，该因子在内耳毛细胞的祖细胞，小脑颗粒细胞，脊髓背膜中间神经元中表达，几个脑干核，脑干核，Merkel细胞，默克尔细胞和肠道菌的分泌细胞。 值得注意的是，Math1和Hath1的表达分别在小鼠模型和人类样品的髓母细胞瘤中上调。 基因靶向表明，对于许多这些细胞的起源，MATH1是必需的。 然而，这些细胞种群中的一些在产后区分，并且由于Math1 Null小鼠在出生时死于无法呼吸，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细胞的命运，我们将诱导型CRE重组酶靶向于Math1基因组基因座。 当这些小鼠越过报告菌株时，此Cre/LoxP系统将永久标记表达数学的细胞，以便可以将它们的整个下游谱系追溯到成年。 我们还将使用现有的条件等位基因在特定的胚胎和产后时间点删除脑干中的Math1，并在MATH1 NULL中识别呼吸缺陷所需的脑干核，并研究Math1在小脑颗粒颗粒细胞增殖和分化中的作用。 这些命运映射和条件敲除研究的结合应提供有关表达数学细胞类型的发展，呼吸的启动以及神经元祖细胞增殖和分化之间的联系的基本知识。 这些信息可能会洞悉诸如髓母细胞瘤和围产期呼吸道功能障碍之类的后脑疾病，例如猝死综合症。