Abnormal embryonic cerebellar development and patterning of postnatal foliation in two mouse Engrailed-2 mutants.
Abnormal embryonic cerebellar development and patterning of postnatal foliation in two mouse Engrailed-2 mutants.
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发表时间：
1994-03
期刊：
影响因子：
4.6
通讯作者：
K. Millen;W. Wurst;K. Herrup;A. Joyner
中科院分区：
文献类型：
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作者：
K. Millen;W. Wurst;K. Herrup;A. Joyner
小脑是研究中枢神经系统模式形成的理想系统，因为其简单的细胞结构和规则的褶皱和神经回路组织。Engrailed-2（En-2）在中脑-后脑连接处（小脑起源的区域）周围的空间限制性宽带中表达。En-2同源异型框（En-2 hd）靶向缺失的纯合子小鼠先前已被证明具有改变的成人小脑叶状模式。为了解决En-2 hd等位基因是否是亚型的，我们产生了一个推定的无效突变，使N-末端缺失（ntd）。这种新突变En-2ntd的纯合子小鼠显示出相同的小脑模式缺陷，表明两个等位基因都代表无效等位基因。我们还检查了En-2纯合突变体小脑叶状结构的发育概况。这揭示了一个复杂的表型的一般发育迟缓和异常形成的特定裂缝与最严重的形态中断被限制在小脑的后部区域。还发现En-2纯合子中两种转基因的表达也发生了变化，这表明可能存在脑叶转化，这两种转基因在小脑中以脑叶特异性模式表达lacZ。最后，在胚胎发生过程中，中线处小脑雏形的融合明显延迟至15.5 d.p.c.。这和En-2的表达模式表明，虽然小脑叶形成主要是一个出生后的过程，小脑的图案可能开始在胚胎发育过程中，En-2起着至关重要的作用，在这个早期过程。
The cerebellum is an ideal system to study pattern formation in the central nervous system because of its simple cytoarchitecture and regular organization of folds and neural circuitry. Engrailed-2 (En-2) is expressed in a spatially restricted broad band around the mesencephalic-metencephalic junction, a region from which the cerebellum is derived. Mice homozygous for a targeted deletion of the En-2 homeobox, En-2hd, previously have been shown to have an altered adult cerebellar foliation pattern. To address whether the En-2hd allele was hypomorphic, we generated a putative null mutation that makes an N-terminal deletion (ntd). Mice homozygous for this new mutation, En-2ntd, display an identical cerebellar patterning defect, suggesting that both alleles represent null alleles. We also examined the developmental profile of En-2 homozygous mutant cerebellar foliation. This revealed a complex phenotype of general developmental delay and abnormal formation of specific fissures with the most severe morphological disruptions being limited to the posterior region of the cerebellum. The expression of two transgenes, which express lacZ in lobe-specific patterns in the cerebellum, also was found to be altered in En-2 homozygotes, suggesting possible lobe transformations. Finally, during embryogenesis there was a clear delay in fusion of the cerebellar rudiments at the midline by 15.5 d.p.c. This and the expression pattern of En-2 suggests that although cerebellar foliation is largely a postnatal process, the patterning of the cerebellum may begin during embryogenesis and that En-2 plays a critical role in this early process.