Engrailed homeobox genes regulate establishment of the cerebellar afferent circuit map.
Engrailed homeobox genes regulate establishment of the cerebellar afferent circuit map.
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DOI：
10.1523/jneurosci.0653-10.2010
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发表时间：
2010-07-28
期刊：
影响因子：
--
通讯作者：
Joyner AL
中科院分区：
文献类型：
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作者：
Sillitoe RV;Vogel MW;Joyner AL
小脑传入图的空间组织与小脑内内在模式的两个方面具有显着的对应性，这两个方面由一系列小叶和浦肯野细胞（PC）条纹基因表达体现。我们使用雄性和雌性小鼠测试了 Engrailed (En) 同源框基因是否是调节所有三个系统的常见遗传底物，因为它们在小脑内的空间受限区域中表达，并且对于 PC 基因表达和叶化的模式至关重要。事实上，我们发现 En1/2 对于将苔藓纤维精确定位到不同的小叶以及随后将其解析为离散的旁矢状带是必需的。此外，每个 En 基因协调调节传入靶向和 PC 蛋白表达的条纹模式（例如 ZebrinII/AldolaseC），独立于调节叶状结构。我们进一步发现，En1/2，而不是完整的小叶的存在，对于产生 PC 蛋白条纹和苔藓纤维带至关重要，并且 PC 条纹基因表达是在传入带之前确定的。因此，En转录因子不仅调节小脑回路拓扑，而且它们还足够精确地连接传入和传出神经元，使得PC蛋白表达的改变可以用作回路中潜在缺陷的读数。总之，我们的数据表明 En1/2 是小脑 3 维组织的主要调节因子，并协调调节形态、模式基因表达和传入地形。
The spatial organization of the cerebellar afferent map has remarkable correspondence to two aspects of intrinsic patterning within the cerebellum embodied by a series of lobules and Purkinje cell (PC) striped gene expression. Using male and female mice we tested whether the Engrailed (En) homeobox genes are a common genetic substrate regulating all three systems, since they are expressed in spatially restricted domains within the cerebellum and are critical for patterning PC gene expression and foliation. Indeed, we discovered that En1/2 are necessary for the precise targeting of mossy fibers to distinct lobules, as well as their subsequent resolution into discrete parasagittal bands. Moreover, each En gene coordinately regulates afferent targeting and the striped pattern of PC protein expression (e.g. ZebrinII/AldolaseC) independent of regulating foliation. We further found that En1/2, rather than the presence of a full complement of lobules are critical for generating PC protein stripes and mossy fiber bands, and that PC striped gene expression is determined prior to afferent banding. Thus, the En transcription factors not only regulate cerebellum circuit topography, but they also link afferent and efferent neurons precisely enough that alterations in PC protein expression can be used as a read out for underlying defects in circuitry. In summary, our data suggests that En1/2 are master regulators of 3-dimensional organization of the cerebellum and coordinately regulate morphology, patterned gene expression and afferent topography.