PUBLICATION

A bi-modal function of Wnt signalling directs an FGF activity gradient to spatially regulate neuronal differentiation in the midbrain

Authors
Dyer, C., Blanc, E., Hanisch, A., Roehl, H., Otto, G.W., Yu, T., Basson, M.A., and Knight, R.
ID
ZDB-PUB-140113-29
Date
2014
Source
Development (Cambridge, England)   141(1): 63-72 (Journal)
Registered Authors
Knight, Robert, Otto, Georg, Roehl, Henry
Keywords
Chemical genetics, Hairy, Mathematical modelling, Neurogenesis, Sprouty, Zebrafish
MeSH Terms
  • Nerve Tissue Proteins/metabolism
  • Mice, Knockout
  • Mice
  • Gene Expression Regulation, Developmental
  • Fibroblast Growth Factors/metabolism*
  • Neurogenesis
  • Wnt Signaling Pathway/physiology*
  • Neural Stem Cells/metabolism*
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors/biosynthesis
  • Basic Helix-Loop-Helix Transcription Factors/metabolism*
  • Zebrafish
  • Mesencephalon/embryology*
  • Mesencephalon/growth & development
  • Mesencephalon/metabolism
  • Zebrafish Proteins/biosynthesis
  • Zebrafish Proteins/metabolism*
  • Cell Movement
(all 18)
PubMed
24284206 Full text @ Development
Abstract

FGFs and Wnts are important morphogens during midbrain development, but their importance and potential interactions during neurogenesis are poorly understood. We have employed a combination of genetic and pharmacological manipulations in zebrafish to show that during neurogenesis FGF activity occurs as a gradient along the anterior-posterior axis of the dorsal midbrain and directs spatially dynamic expression of the Hairy gene her5. As FGF activity diminishes during development, Her5 is lost and differentiation of neuronal progenitors occurs in an anterior-posterior manner. We generated mathematical models to explain how Wnt and FGFs direct the spatial differentiation of neurons in the midbrain through Wnt regulation of FGF signalling. These models suggested that a negative-feedback loop controlled by Wnt is crucial for regulating FGF activity. We tested Sprouty genes as mediators of this regulatory loop using conditional mouse knockouts and pharmacological manipulations in zebrafish. These reveal that Sprouty genes direct the positioning of early midbrain neurons and are Wnt responsive in the midbrain. We propose a model in which Wnt regulates FGF activity at the isthmus by driving both FGF and Sprouty gene expression. This controls a dynamic, posteriorly retracting expression of her5 that directs neuronal differentiation in a precise spatiotemporal manner in the midbrain.

Genes / Markers
Figures
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
cj4TgTransgenic Insertion
    kca4TgTransgenic Insertion
      knu3TgTransgenic Insertion
        ne1939TgTransgenic Insertion
          ot1TgTransgenic Insertion
            pd1TgTransgenic Insertion
              ti282a
                Point Mutation
                tu29a
                  Point Mutation
                  w25TgTransgenic Insertion
                    w32TgTransgenic Insertion
                      1 - 10 of 11
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                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      Target Reagent Reagent Type
                      her5MO1-her5MRPHLNO
                      1 - 1 of 1
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                      Fish
                      Antibodies
                      Orthology
                      No data available
                      Engineered Foreign Genes
                      Marker Marker Type Name
                      EGFPEFGEGFP
                      GAL4EFGGAL4
                      GFPEFGGFP
                      1 - 3 of 3
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                      Mapping
                      No data available