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）：小鼠无调性同源物 1 (Math1) 编码一种基本的螺旋-环-螺旋转录因子，在内耳毛细胞、小脑颗粒细胞、脊髓背侧中间神经元、多个脑干的祖细胞中表达细胞核、默克尔细胞和肠道的分泌细胞。 还值得注意的是，Math1 和 HATH1 的表达在小鼠模型和人类样本的髓母细胞瘤中分别上调。 基因打靶已证明 Math1 对于许多此类细胞的形成是必需的。 然而，其中一些细胞群在出生后发生分化，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 功能的依赖性尚未得到充分分析。 为了研究所有表达 Math1 的细胞的命运，我们将诱导型 Cre 重组酶靶向 Math1 基因组位点。 当这些小鼠与报告菌株杂交时，这个 Cre/loxP 系统将永久标记 Math1 表达细胞，以便可以追踪它们的整个下游谱系直至成年。 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，以便识别Math1缺失中呼吸缺陷所需的脑干核，并研究Math1在小脑颗粒细胞中的作用增殖和分化。 这些命运图谱和条件敲除研究的结合应该提供关于表达 Math1 的细胞类型的发育、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础知识。 这些信息可能有助于深入了解髓母细胞瘤等后脑疾病和婴儿猝死综合症等围产期呼吸功能障碍。