Li Shengguo, Qiu Feng, Xu Anlong, Price Sandy M, Xiang Mengqing
Center for Advanced Biotechnology and Medicine and Department of Pediatrics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
J Neurosci. 2004 Mar 24;24(12):3104-14. doi: 10.1523/JNEUROSCI.4444-03.2004.
The neurons generated at the germinal rhombic lip undergo long distance migration along divergent pathways to settle in widely dispersed locations within the hindbrain, giving rise to cerebellar granule cells and precerebellar nuclei. Neurotrophin-3 (NT-3) signaling has been shown to be required for proper migration and survival of cerebellar granule cells. The molecular bases that govern NT-3 expression within the cerebellum, however, remain unknown at present. Here we report that, during early mouse neurogenesis, the Barhl1 homeobox gene is highly expressed by the rhombic lip and rhombic lip-derived migratory neurons. Its expression is later restricted to cerebellar granule cells and precerebellar neurons extending mossy fibers, two groups of neurons that synaptically connect in the adult cerebellar system. Loss of Barhl1 function causes cerebellar phenotypes with a striking similarity to those of NT-3 conditional null mice, which include attenuated cerebellar foliation as well as defective radial migration and increased apoptotic death of granule cells. Correlating with these defects, we find that NT-3 expression is dramatically downregulated in granule cells of the posterior lobe of Barhl1(-)/- cerebella. Moreover, in the precerebellar system of Barhl1(-/-) mice, all five nuclei that project mossy fibers fail to form correctly because of aberrant neuronal migration and elevated apoptosis. These results suggest that Barhl1 plays an essential role in the migration and survival of cerebellar granule cells and precerebellar neurons and functionally link Barhl1 to the NT-3 signaling pathway during cerebellar development.
在生发菱唇处产生的神经元沿着不同的路径进行长距离迁移，定居在后脑广泛分散的位置，从而产生小脑颗粒细胞和小脑前核。神经营养因子3（NT-3）信号已被证明是小脑颗粒细胞正常迁移和存活所必需的。然而，目前尚不清楚调控小脑内NT-3表达的分子基础。在此我们报告，在小鼠早期神经发生过程中，Barhl1同源框基因在菱唇和菱唇衍生的迁移神经元中高度表达。其表达后来局限于小脑颗粒细胞和延伸苔藓纤维的小脑前神经元，这两组神经元在成年小脑系统中形成突触连接。Barhl1功能缺失导致的小脑表型与NT-3条件性敲除小鼠的表型惊人地相似，包括小脑叶片发育减弱以及颗粒细胞的放射状迁移缺陷和凋亡死亡增加。与这些缺陷相关的是，我们发现Barhl1(-)/-小鼠小脑后叶颗粒细胞中NT-3表达显著下调。此外，在Barhl1(-/-)小鼠的小脑前系统中，所有投射苔藓纤维的五个核由于异常的神经元迁移和凋亡增加而未能正确形成。这些结果表明，Barhl1在小脑颗粒细胞和小脑前神经元的迁移和存活中起重要作用，并在小脑发育过程中在功能上将Barhl1与NT-3信号通路联系起来。
