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First published online 13 December 2006
doi: 10.1242/dev.02745
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1 Institute of Neuroscience and Key Laboratory of Neurobiology, Shanghai
Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai
200031, China.
2 Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School
of Medicine, Shanghai 200025, China.
3 Department of Biochemistry and Molecular Biology, University of Texas, MD
Anderson Cancer Center, Houston, TX 77030, USA.
4 Departments of Anesthesiology, Psychiatry, Molecular Biology and Pharmacology,
School of Medicine Pain Center, Washington University, St Louis, MO 63110,
USA.
Author for correspondence (e-mail:
dingyq{at}ion.ac.cn)
Accepted 15 November 2006
Secreted factors FGF8 and WNT1 are essential either for the inductive activity of the isthmus organizer or for the regionalization of the midbrain-hindbrain boundary (MHB). However, transcriptional regulation of these secreted factors during development remains to be elucidated. Here we show that the LIM homeobox gene Lmx1b is expressed in the anterior embryo as early as E7.5 and its expression becomes progressively restricted to the isthmus at E9.0. Analysis of gene expression in the MHB of the mutant embryos showed that many genes were lost by E9.5. In the MHB of Lmx1b-/- embryos, the expression of Fgf8, which normally occurs at the 4-somite stage, was completely absent, whereas Wnt1 was downregulated before the 4-somite stage. Moreover, transcription factors En1 and Pax2 were also downregulated prior to the 4-somite stage, whereas Gbx2 downregulation occurred at the 4-somite stage. By contrast, Otx2 and Pax6 expression was not affected in Lmx1b-/- embryos. The requirement of specific Lmx1b expression in the MHB was further confirmed by Wnt1-Cre-mediated region-specific conditional knockout of Lmx1b. As a result of these molecular defects, the development of the tectum and cerebellum was severely impaired in Lmx1b-/- mice. Taken together, our results indicate that Lmx1b plays an essential role in the development of the tectum and cerebellum by regulating expression of Fgf8, Wnt1 and several isthmus-related transcription factors in the MHB, and is a crucial component of a cross-regulatory network required for the induction activity of the isthmic organizer in the MHB.
Key words: Lmx1b, Isthmic organizer, Fgf8, Tectum, Cerebellum
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