PUBLICATION

Gsk3{beta}/PKA and Gli1 regulate the maintenance of neural progenitors at the midbrain-hindbrain boundary in concert with E(Spl) factor activity

Authors
Ninkovic, J., Stigloher, C., Lillesaar, C., and Bally-Cuif, L.
ID
ZDB-PUB-080902-9
Date
2008
Source
Development (Cambridge, England)   135(18): 3137-3148 (Journal)
Registered Authors
Bally-Cuif, Laure, Lillesaar, Christina, Ninkovic, Jovica, Stigloher, Christian
Keywords
E(Spl), Her5, Her11, Zebrafish, Midbrain-hindbrain boundary, Neural progenitor, Gsk3β, PKA, Gli1
MeSH Terms
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Animals
  • Neurons/metabolism
  • Neurons/physiology*
  • In Situ Hybridization
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Mesencephalon/embryology*
  • Mesencephalon/metabolism
  • Mesencephalon/physiology
  • Nervous System/metabolism
  • Embryo, Nonmammalian
  • Rhombencephalon/embryology*
  • Rhombencephalon/metabolism
  • Rhombencephalon/physiology
  • Stem Cells/cytology
  • Stem Cells/physiology*
  • Models, Biological
  • Trans-Activators/genetics
  • Trans-Activators/metabolism*
  • Oncogene Proteins/genetics
  • Oncogene Proteins/metabolism*
  • Animals, Genetically Modified
  • Immunohistochemistry
  • Basic Helix-Loop-Helix Transcription Factors/genetics
  • Basic Helix-Loop-Helix Transcription Factors/metabolism*
  • Cyclic AMP-Dependent Protein Kinases/genetics
  • Cyclic AMP-Dependent Protein Kinases/metabolism*
(all 30)
PubMed
18725518 Full text @ Development
Abstract
Neuronal production in the midbrain-hindbrain domain (MH) of the vertebrate embryonic neural tube depends on a progenitor pool called the 'intervening zone' (IZ), located at the midbrain-hindbrain boundary. The progressive recruitment of IZ progenitors along the mediolateral (future dorsoventral) axis prefigures the earlier maturation of the MH basal plate. It also correlates with a lower sensitivity of medial versus lateral IZ progenitors to the neurogenesis inhibition process that maintains the IZ pool. This role is performed in zebrafish by the E(Spl) factors Her5 and Her11, but the molecular cascades cooperating with Her5/11, and those accounting for their reduced effect in the medial IZ, remain unknown. We demonstrate here that the kinases Gsk3beta and cAMP-dependent protein kinase A (PKA) are novel determinants of IZ formation and cooperate with E(Spl) activity in a dose-dependent manner. Similar to E(Spl), we show that the activity of Gsk3beta/PKA is sensed differently by medial versus lateral IZ progenitors. Furthermore, we identify the transcription factor Gli1, expressed in medial IZ cells, as an antagonist of E(Spl) and Gsk3beta/PKA, and demonstrate that the neurogenesis-promoting activity of Gli1 accounts for the reduced sensitivity of medial IZ progenitors to neurogenesis inhibitors and their increased propensity to differentiate. We also show that the expression and activity of Gli1 in this process are, surprisingly, independent of Hedgehog signaling. Together, our results suggest a model in which the modulation of E(Spl) and Gsk3beta/PKA activities by Gli1 underlies the dynamic properties of IZ maintenance and recruitment.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
Gene Antibody Fish Conditions Stage Qualifier Anatomy Assay Figure
EGFPne1939Tg (AB)standard conditions90%-epibolyIFL
EGFPne1939Tg (AB)standard conditions1-4 somitesIFL
EGFPne1939Tg (AB)standard conditionsBudIFL
EGFPne1939Tg (AB)standard conditionsBudIFL
gli1ABchemical treatment: Cyclopamine75%-epibolyISH
gli1ABstandard conditions75%-epibolyISH
gli1ABstandard conditionsBudISH
gli1ABchemical treatment: Cyclopamine1-4 somitesISH
gli1ABstandard conditions1-4 somitesISH
gli1ABchemical treatment: CyclopamineBudISH
1 - 10 of 58
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Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
b641
    		Point Mutation
    ne1939TgTransgenic Insertion
      w5
        		Deficiency
        w26TgTransgenic Insertion
          1 - 4 of 4
          Show
          Human Disease / Model
          No data available
          Sequence Targeting Reagents
          Target Reagent Reagent Type
          gli1MO1-gli1MRPHLNO
          1 - 1 of 1
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          Fish
          Fish
          AB
          AB + MO1-gli1
          Df(Chr23:acvr1ba,sp5l,wnt1,wnt10b)w5/w5 (AB)
          ne1939Tg (AB)
          smob641/b641 (AB)
          w26Tg (AB)
          1 - 6 of 6
          Show
          Antibodies
          Orthology
          No data available
          Engineered Foreign Genes
          Marker Marker Type Name
          EGFPEFGEGFP
          GFPEFGGFP
          1 - 2 of 2
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          Mapping
          No data available
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          Citation
          Ninkovic, J., Stigloher, C., Lillesaar, C., and Bally-Cuif, L. (2008) Gsk3{beta}/PKA and Gli1 regulate the maintenance of neural progenitors at the midbrain-hindbrain boundary in concert with E(Spl) factor activity. Development (Cambridge, England). 135(18):3137-3148.