title: Lmx1b is essential for Fgf8 and Wnt1 expression in the isthmic organizer during tectum and cerebellum development in mice.
abstract: 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.
authors.affiliation: Institute of Neuroscience and Key Laboratory of Neurobiology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Guo
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Qiu
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Haixu
authors.initials: H
authors.lastname: Chen
authors.forename: Rong-Qiang
authors.initials: RQ
authors.lastname: Yang
authors.forename: Sheng-Di
authors.initials: SD
authors.lastname: Chen
authors.forename: Randy L
authors.initials: RL
authors.lastname: Johnson
authors.forename: Zhou-Feng
authors.initials: ZF
authors.lastname: Chen
authors.forename: Yu-Qiang
authors.initials: YQ
authors.lastname: Ding
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism*; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D017403:In Situ Hybridization; D060850:LIM-Homeodomain Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010641:Phenotype; D011247:Pregnancy; D003336:Tectum Mesencephali / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051155:Wnt1 Protein / Q000235:genetics*
chemical_list: C496457:Fgf8 protein, mouse; D018398:Homeodomain Proteins; C112149:LIM homeobox transcription factor 1 beta; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D051524:Fibroblast Growth Factor 8