Urbánek P, Fetka I, Meisler M H, Busslinger M
Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria.
Proc Natl Acad Sci U S A. 1997 May 27;94(11):5703-8. doi: 10.1073/pnas.94.11.5703.
Midbrain and cerebellum development depends on an organizing center that is located at the midbrain-hindbrain junction of the vertebrate embryo. Expression of the two closely related transcription factors Pax2 and Pax5 overlaps spatially and temporally in this region of the developing central nervous system. To study a possible interaction of these transcription factors in midbrain and cerebellum patterning, we have generated Pax5, Krd double mutant mice. The transgene-induced Krd mutation corresponds to an approximately 7-centimorgan chromosome 19 deletion that eliminates the entire Pax2 locus. The heterozygous Krd mutation deleting one Pax2 allele had no effect on midbrain and cerebellum development. Moreover, only minor developmental defects were previously observed at the midline of the inferior colliculus and anterior cerebellum in mice that were homozygous for a targeted Pax5 mutation. Similar morphological alterations were observed in 80% of all compound heterozygous Pax5 (+/-) Krd (+/-) mice. However, in the remaining 20% of compound heterozygotes, the inferior colliculi were missing, and the vermis of the cerebellum was severely disrupted due to the failure of the cerebellar primordia to fuse at the midline. Inactivation of the second Pax5 allele in Pax5 (-/-) Krd (+/-) mice resulted in complete loss of the posterior midbrain and cerebellum, as the tissue originating from the midbrain-hindbrain boundary region was deleted in the embryo as early as day 9.5. On the basis of these data, we propose that the cooperation of Pax2 and Pax5 is essential for normal functioning of the organizing center at the midbrain-hindbrain junction.
中脑和小脑的发育依赖于一个位于脊椎动物胚胎中脑-后脑交界处的组织中心。在发育中的中枢神经系统的这个区域，两个密切相关的转录因子Pax2和Pax5的表达在空间和时间上重叠。为了研究这些转录因子在中脑和小脑模式形成中可能的相互作用，我们构建了Pax5、Krd双突变小鼠。转基因诱导的Krd突变对应于19号染色体上约7厘摩的缺失，该缺失消除了整个Pax2基因座。缺失一个Pax2等位基因的杂合Krd突变对中脑和小脑发育没有影响。此外，先前在靶向Pax5突变纯合的小鼠的下丘和前小脑的中线处仅观察到轻微的发育缺陷。在所有复合杂合Pax5(+/-)Krd(+/-)小鼠中，80%观察到了类似的形态改变。然而，在其余20%的复合杂合子中，下丘缺失，小脑蚓部严重紊乱，因为小脑原基在中线处未能融合。在Pax5(-/-)Krd(+/-)小鼠中使第二个Pax5等位基因失活导致中脑后部和小脑完全缺失，因为早在胚胎第9.5天，源自中脑-后脑边界区域的组织就被删除了。基于这些数据，我们提出Pax2和Pax5的合作对于中脑-后脑交界处组织中心的正常功能至关重要。
