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Alexandra L Joyner - One of the best experts on this subject based on the ideXlab platform.

  • en and gbx2 play essential roles downstream of fgf8 in patterning the mouse mid hindbrain region
    Development, 2001
    Co-Authors: Aimin Liu, Alexandra L Joyner
    Abstract:

    Fgf8, which is expressed at the embryonic mid/hindbrain junction, is required for and sufficient to induce the formation of midbrain and cerebellar structures. To address through what genetic pathways FGF8 acts, we examined the epistatic relationships of mid/hindbrain genes that respond to FGF8, using a novel mouse brain explant culture system. We found that En2 and Gbx2 are the first genes to be induced by FGF8 in wild-type E9.5 diencephalic and midbrain explants treated with FGF8-soaked beads. By examining gene expression in En1/2 double mutant mouse embryos, we found that Fgf8, Wnt1 and Pax5 do not require the En genes for initiation of expression, but do for their maintenance, and Pax6 expression is expanded caudally into the midbrain in the absence of EN function. Since E9.5 En1/2 double mutants lack the mid/hindbrain region, forebrain mutant explants were treated with FGF8 and, significantly, the EN transcription factors were found to be required for induction of Pax5. Thus, FGF8-regulated expression of Pax5 is dependent on EN proteins, and a factor other than FGF8 could be involved in initiating normal Pax5 expression in the Mesencephalon/metencephalon. The En genes also play an important, but not absolute, role in repression of Pax6 in forebrain explants by FGF8. Previous Gbx2 gain-of-function studies have shown that misexpression of Gbx2 in the midbrain can lead to repression of Otx2. However, in the absence of Gbx2, FGF8 can nevertheless repress Otx2 expression in midbrain explants. In contrast, Wnt1 is initially broadly induced in Gbx2 mutant explants, as in wild-type explants, but not subsequently repressed in cells near FGF8 that normally express Gbx2. Thus GBX2 acts upstream of, or parallel to, FGF8 in repressing Otx2, and acts downstream of FGF8 in repression of Wnt1. This is the first such epistatic study performed in mouse that combines gain-of-function and loss-of-function approaches to reveal aspects of mouse gene regulation in the Mesencephalon/metencephalon that have been difficult to address using either approach alone.

  • engrailed wnt and pax genes regulate midbrain hindbrain development
    Trends in Genetics, 1996
    Co-Authors: Alexandra L Joyner
    Abstract:

    Abstract The mouse Engrailed, Wnt and Pax genes, which are homologues of Drosophila segmentation genes, have provided a critical genetic entry point for dissecting the molecular and cellular control of Mesencephalon and metencephalon development in vertebrates. Mutant phenotypes and gene expression data suggest that six members of these gene families are required for early formation of these brain regions. Ectopic transplantation studies have shown that the midbrain-hindbrain-junction portion can act as an organizer and recruit certain host cells to re-establish parts of the entire region. Taken together, these studies indicate that the Mesencephalon and metencephalon develop as one independent unit, and that the genetic network regulating development of this region involves conserved genes that control segmentation in Drosophila. By analogy, segmentation of the rest of the brain might best be described in terms of ‘genetic units’ defined by genetic and transplantation data.

  • Engrailed, Wnt and Pax genes regulate midbrain-hindbrain development
    Trends in genetics : TIG, 1996
    Co-Authors: Alexandra L Joyner
    Abstract:

    The mouse Engrailed, Wnt and Pax genes, which are homologues of Drosophila segmentation genes, have provided a critical genetic entry point for dissecting the molecular and cellular control of Mesencephalon and metencephalon development in vertebrates. Mutant phenotypes and gene expression data suggest that six members of these gene families are required for early formation of these brain regions. Ectopic transplantation studies have shown that the midbrain-hindbrain-junction protein can act as an organizer and recruit certain host cells to re-establish parts of the entire region. Taken together, these studies indicate that the Mesencephalon and metencephalon develop as one independent unit, and that the genetic network regulating development of this region involves conserved genes that control segmentation in Drosophila. By analogy, segmentation of the rest of the brain might best be described in terms of 'genetic units' defined by genetic and transplantation data.

Salvador Martinez - One of the best experts on this subject based on the ideXlab platform.

  • positional regulation of pax2 expression pattern in mesencephalic and diencephalic alar plate
    Neuroscience, 2006
    Co-Authors: Claudia Vieira, Raquel Garcialopez, Salvador Martinez
    Abstract:

    Regionalization of the neural tube is a fundamental event in the development of the CNS. The isthmic organizer controls the development of the mesencephalic-rhombencephalic junction by means of fibroblast growth factor 8 (Fgf8) expression. The transcription factor paired box 2 (Pax2) is expressed early in the midbrain and is later progressively restricted to the mid-hindbrain region, playing an important role in the development of the Mesencephalon and the cerebellum. In this study, by implanting Fgf8-beads in the chick neural tube, we show that Fgf8 induces a heterogeneous pattern of Pax2 expression in the diencephalon. To explore the mechanisms controlling this asymmetric induction and the down-regulation of Pax2 in the anterior Mesencephalon we performed antero-posterior inversions of diencephalic and/or mesencephalic neuroepithelium, with or without Fgf8-bead implantation. We show that anterior factors do not play a role in Pax2 regionalization, while posterior factors could explain these expression patterns. We conclude that the anterior Mesencephalon and the diencephalon are able to retain or activate Pax2 expression under caudal influences, and to develop as a tectal structure at later developmental stages.

  • the isthmic organizer signal fgf8 is required for cell survival in the prospective midbrain and cerebellum
    Development, 2003
    Co-Authors: Salvador Martinez, Wolfgang Wurst, Gail R Martin
    Abstract:

    Numerous studies have demonstrated that the midbrain and cerebellum develop from a region of the early neural tube comprising two distinct territories known as the Mesencephalon (mes) and rostral metencephalon (met; rhombomere 1), respectively. Development of the mes and met is thought to be regulated by molecules produced by a signaling center, termed the isthmic organizer (IsO), which is localized at the boundary between them. FGF8 and WNT1 have been implicated as key components of IsO signaling activity, and previous studies have shown that in Wnt1 -/- embryos, the mes/met is deleted by the 30 somite stage (∼E10) (McMahon, A. P. and Bradley, A. ([1990][1]) Cell 62, 1073-1085). We have studied the function of FGF8 in mouse mes/met development using a conditional gene inactivation approach. In our mutant embryos, Fgf8 expression was transiently detected, but then was eliminated in the mes/met by the 10 somite stage (∼E8.75). This resulted in a failure to maintain expression of Wnt1 as well as Fgf17, Fgf18 , and Gbx2 in the mes/met at early somite stages, and in the absence of the midbrain and cerebellum at E17.5. We show that a major cause of the deletion of these structures is ectopic cell death in the mes/met between the 7 and 30 somite stages. Interestingly, we found that the prospective midbrain was deleted at an earlier stage than the prospective cerebellum. We observed a remarkably similar pattern of cell death in Wnt1 null homozygotes, and also detected ectopic mes/met cell death in En1 null homozygotes. Our data show that Fgf8 is part of a complex gene regulatory network that is essential for cell survival in the mes/met. [1]: #ref-38

  • The isthmic organizer signal FGF8 is required for cell survival in the prospective midbrain and cerebellum.
    Development (Cambridge England), 2003
    Co-Authors: Candace L. Chi, Wolfgang Wurst, Salvador Martinez, Gail R Martin
    Abstract:

    Numerous studies have demonstrated that the midbrain and cerebellum develop from a region of the early neural tube comprising two distinct territories known as the Mesencephalon (mes) and rostral metencephalon (met; rhombomere 1), respectively. Development of the mes and met is thought to be regulated by molecules produced by a signaling center, termed the isthmic organizer (IsO), which is localized at the boundary between them. FGF8 and WNT1 have been implicated as key components of IsO signaling activity, and previous studies have shown that in Wnt1(-/-) embryos, the mes/met is deleted by the 30 somite stage ( approximately E10) (McMahon, A. P. and Bradley, A. (1990) Cell 62, 1073-1085). We have studied the function of FGF8 in mouse mes/met development using a conditional gene inactivation approach. In our mutant embryos, Fgf8 expression was transiently detected, but then was eliminated in the mes/met by the 10 somite stage ( approximately E8.75). This resulted in a failure to maintain expression of Wnt1 as well as Fgf17, Fgf18, and Gbx2 in the mes/met at early somite stages, and in the absence of the midbrain and cerebellum at E17.5. We show that a major cause of the deletion of these structures is ectopic cell death in the mes/met between the 7 and 30 somite stages. Interestingly, we found that the prospective midbrain was deleted at an earlier stage than the prospective cerebellum. We observed a remarkably similar pattern of cell death in Wnt1 null homozygotes, and also detected ectopic mes/met cell death in En1 null homozygotes. Our data show that Fgf8 is part of a complex gene regulatory network that is essential for cell survival in the mes/met.

Gail R Martin - One of the best experts on this subject based on the ideXlab platform.

  • the isthmic organizer signal fgf8 is required for cell survival in the prospective midbrain and cerebellum
    Development, 2003
    Co-Authors: Salvador Martinez, Wolfgang Wurst, Gail R Martin
    Abstract:

    Numerous studies have demonstrated that the midbrain and cerebellum develop from a region of the early neural tube comprising two distinct territories known as the Mesencephalon (mes) and rostral metencephalon (met; rhombomere 1), respectively. Development of the mes and met is thought to be regulated by molecules produced by a signaling center, termed the isthmic organizer (IsO), which is localized at the boundary between them. FGF8 and WNT1 have been implicated as key components of IsO signaling activity, and previous studies have shown that in Wnt1 -/- embryos, the mes/met is deleted by the 30 somite stage (∼E10) (McMahon, A. P. and Bradley, A. ([1990][1]) Cell 62, 1073-1085). We have studied the function of FGF8 in mouse mes/met development using a conditional gene inactivation approach. In our mutant embryos, Fgf8 expression was transiently detected, but then was eliminated in the mes/met by the 10 somite stage (∼E8.75). This resulted in a failure to maintain expression of Wnt1 as well as Fgf17, Fgf18 , and Gbx2 in the mes/met at early somite stages, and in the absence of the midbrain and cerebellum at E17.5. We show that a major cause of the deletion of these structures is ectopic cell death in the mes/met between the 7 and 30 somite stages. Interestingly, we found that the prospective midbrain was deleted at an earlier stage than the prospective cerebellum. We observed a remarkably similar pattern of cell death in Wnt1 null homozygotes, and also detected ectopic mes/met cell death in En1 null homozygotes. Our data show that Fgf8 is part of a complex gene regulatory network that is essential for cell survival in the mes/met. [1]: #ref-38

  • The isthmic organizer signal FGF8 is required for cell survival in the prospective midbrain and cerebellum.
    Development (Cambridge England), 2003
    Co-Authors: Candace L. Chi, Wolfgang Wurst, Salvador Martinez, Gail R Martin
    Abstract:

    Numerous studies have demonstrated that the midbrain and cerebellum develop from a region of the early neural tube comprising two distinct territories known as the Mesencephalon (mes) and rostral metencephalon (met; rhombomere 1), respectively. Development of the mes and met is thought to be regulated by molecules produced by a signaling center, termed the isthmic organizer (IsO), which is localized at the boundary between them. FGF8 and WNT1 have been implicated as key components of IsO signaling activity, and previous studies have shown that in Wnt1(-/-) embryos, the mes/met is deleted by the 30 somite stage ( approximately E10) (McMahon, A. P. and Bradley, A. (1990) Cell 62, 1073-1085). We have studied the function of FGF8 in mouse mes/met development using a conditional gene inactivation approach. In our mutant embryos, Fgf8 expression was transiently detected, but then was eliminated in the mes/met by the 10 somite stage ( approximately E8.75). This resulted in a failure to maintain expression of Wnt1 as well as Fgf17, Fgf18, and Gbx2 in the mes/met at early somite stages, and in the absence of the midbrain and cerebellum at E17.5. We show that a major cause of the deletion of these structures is ectopic cell death in the mes/met between the 7 and 30 somite stages. Interestingly, we found that the prospective midbrain was deleted at an earlier stage than the prospective cerebellum. We observed a remarkably similar pattern of cell death in Wnt1 null homozygotes, and also detected ectopic mes/met cell death in En1 null homozygotes. Our data show that Fgf8 is part of a complex gene regulatory network that is essential for cell survival in the mes/met.

Wolfgang Wurst - One of the best experts on this subject based on the ideXlab platform.

  • the isthmic organizer signal fgf8 is required for cell survival in the prospective midbrain and cerebellum
    Development, 2003
    Co-Authors: Salvador Martinez, Wolfgang Wurst, Gail R Martin
    Abstract:

    Numerous studies have demonstrated that the midbrain and cerebellum develop from a region of the early neural tube comprising two distinct territories known as the Mesencephalon (mes) and rostral metencephalon (met; rhombomere 1), respectively. Development of the mes and met is thought to be regulated by molecules produced by a signaling center, termed the isthmic organizer (IsO), which is localized at the boundary between them. FGF8 and WNT1 have been implicated as key components of IsO signaling activity, and previous studies have shown that in Wnt1 -/- embryos, the mes/met is deleted by the 30 somite stage (∼E10) (McMahon, A. P. and Bradley, A. ([1990][1]) Cell 62, 1073-1085). We have studied the function of FGF8 in mouse mes/met development using a conditional gene inactivation approach. In our mutant embryos, Fgf8 expression was transiently detected, but then was eliminated in the mes/met by the 10 somite stage (∼E8.75). This resulted in a failure to maintain expression of Wnt1 as well as Fgf17, Fgf18 , and Gbx2 in the mes/met at early somite stages, and in the absence of the midbrain and cerebellum at E17.5. We show that a major cause of the deletion of these structures is ectopic cell death in the mes/met between the 7 and 30 somite stages. Interestingly, we found that the prospective midbrain was deleted at an earlier stage than the prospective cerebellum. We observed a remarkably similar pattern of cell death in Wnt1 null homozygotes, and also detected ectopic mes/met cell death in En1 null homozygotes. Our data show that Fgf8 is part of a complex gene regulatory network that is essential for cell survival in the mes/met. [1]: #ref-38

  • The isthmic organizer signal FGF8 is required for cell survival in the prospective midbrain and cerebellum.
    Development (Cambridge England), 2003
    Co-Authors: Candace L. Chi, Wolfgang Wurst, Salvador Martinez, Gail R Martin
    Abstract:

    Numerous studies have demonstrated that the midbrain and cerebellum develop from a region of the early neural tube comprising two distinct territories known as the Mesencephalon (mes) and rostral metencephalon (met; rhombomere 1), respectively. Development of the mes and met is thought to be regulated by molecules produced by a signaling center, termed the isthmic organizer (IsO), which is localized at the boundary between them. FGF8 and WNT1 have been implicated as key components of IsO signaling activity, and previous studies have shown that in Wnt1(-/-) embryos, the mes/met is deleted by the 30 somite stage ( approximately E10) (McMahon, A. P. and Bradley, A. (1990) Cell 62, 1073-1085). We have studied the function of FGF8 in mouse mes/met development using a conditional gene inactivation approach. In our mutant embryos, Fgf8 expression was transiently detected, but then was eliminated in the mes/met by the 10 somite stage ( approximately E8.75). This resulted in a failure to maintain expression of Wnt1 as well as Fgf17, Fgf18, and Gbx2 in the mes/met at early somite stages, and in the absence of the midbrain and cerebellum at E17.5. We show that a major cause of the deletion of these structures is ectopic cell death in the mes/met between the 7 and 30 somite stages. Interestingly, we found that the prospective midbrain was deleted at an earlier stage than the prospective cerebellum. We observed a remarkably similar pattern of cell death in Wnt1 null homozygotes, and also detected ectopic mes/met cell death in En1 null homozygotes. Our data show that Fgf8 is part of a complex gene regulatory network that is essential for cell survival in the mes/met.

Andrew P. Mcmahon - One of the best experts on this subject based on the ideXlab platform.

  • Evidence that FGF8 signalling from the midbrain-hindbrain junction regulates growth and polarity in the developing midbrain
    Development (Cambridge England), 1997
    Co-Authors: Scott M. K. Lee, Paul S. Danielian, Bernd Fritzsch, Andrew P. Mcmahon
    Abstract:

    The developing vertebrate Mesencephalon shows a rostrocaudal gradient in the expression of a number of molecular markers and in the cytoarchitectonic differentiation of the tectum, where cells cease proliferating and differentiate in a rostral to caudal progression. Tissue grafting experiments have implicated cell signalling by the mesencephalic-metencephalic (mid-hindbrain) junction (or isthmus) in orchestrating these events. We have explored the role of Wnt-1 and FGF8 signalling in the regulation of mesencephalic polarity. Wnt-1 is expressed in the caudal Mesencephalon and Fgf8 in the most rostral metencephalon. Wnt-1 regulates Fgf8 expression in the adjacent metencephalon, most likely via a secondary mesencephalic signal. Ectopic expression of Fgf8 in the Mesencephalon is sufficient to activate expression of Engrailed-2 (En-2) and ELF-1, two genes normally expressed in a decreasing caudal to rostral gradient in the posterior Mesencephalon. Ectopic expression of Engrailed-1 (En-1), a functionally equivalent homologue of En-2 is sufficient to activate ELF-1 expression by itself. These results indicate the existence of a molecular hierarchy in which FGF8 signalling establishes the graded expression of En-2 within the tectum. This in turn may act to specify other aspects of A-P polarity such as graded ELF-1 expression. Our studies also reveal that FGF8 is a potent mitogen within the Mesencephalon: when ectopically expressed, neural precursors continue to proliferate and neurogenesis is prevented. Taken together our results suggest that FGF8 signalling from the isthmus has a key role in coordinately regulating growth and polarity in the developing Mesencephalon.