PUBLICATION

Modulation of p53 and met expression by krüppel-like factor 8 regulates zebrafish cerebellar development

Authors
Tsai, M., Lu, Y., Liu, Y., Lien, H., Huang, C., Wu, J., Hwang, S.L.
ID
ZDB-PUB-141223-6
Date
2015
Source
Developmental Neurobiology   75(9): 908-26 (Journal)
Registered Authors
Keywords
Klf8, apoptosis, cerebellum, met, p53, zebrafish
MeSH Terms
  • Transcription Factors/metabolism
  • Neurogenesis/physiology
  • Animals
  • Zebrafish
  • Models, Animal
  • Morpholinos
  • Tumor Suppressor Protein p53/metabolism*
  • Apoptosis/physiology
  • Animals, Genetically Modified
  • Proto-Oncogene Proteins c-met/metabolism*
  • Mutation
  • Cerebellum/embryology*
  • Cerebellum/metabolism*
  • Cerebellum/pathology
  • Tectum Mesencephali/embryology
  • Tectum Mesencephali/metabolism
  • Tectum Mesencephali/pathology
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • RNA, Messenger/metabolism
  • Gene Knockdown Techniques
  • Neurons/metabolism
  • Neurons/pathology
  • Neural Stem Cells/physiology
  • Kruppel-Like Transcription Factors/genetics
  • Kruppel-Like Transcription Factors/metabolism*
(all 26)
PubMed
25528982 Full text @ Dev. Neurobiol.
Abstract
Krüppel-like factor 8 (Klf8) is a zinc-finger transcription factor implicated in cell proliferation, and cancer cell survival and invasion; however, little is known about its role in normal embryonic development. Here, we show that Klf8 is required for normal cerebellar development in zebrafish embryos. Morpholino knockdown of klf8 resulted in abnormal cerebellar primordium morphology and the induction of p53 in the brain region at 24 hours post-fertilization (hpf). Both p53-dependent reduction of cell proliferation and augmentation of apoptosis were observed in the cerebellar anlage of 24 hpf-klf8 morphants. In klf8 morphants, expression of ptf1a in the ventricular zone was decreased from 48 to 72 hpf; on the other hand, expression of atohla in the upper rhombic lip was unaffected. Consistent with this finding, Purkinje cell development was perturbed and granule cell number was reduced in 72 hpf-klf8 morphants; co-injection of p53 MO(sp) or klf8 mRNA substantially rescued development of cerebellar Purkinje cells in klf8 morphants. Hepatocyte growth factor (HGF)/Met signaling is known to regulate cerebellar development in zebrafish and mouse. We observed decreased met expression in the tectum and rhombomere 1 of 24 hpf-klf8 morphants, which was largely rescued by co-injection with klf8 mRNA. Moreover, co-injection of met mRNA substantially rescued formation of Purkinje cells in klf8 morphants at 72 hpf. Together, these results demonstrate that Klf8 modulates expression of p53 and met to maintain ptf1a-expressing neuronal progenitors, which are required for the appropriate development of cerebellar Purkinje and granule cells in zebrafish embryos. This article is protected by copyright. All rights reserved.
Genes / Markers
Figures
Figure Gallery (14 images) / 2
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
jh1TgTransgenic Insertion
    1 - 1 of 1
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    Human Disease / Model
    No data available
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    klf8MO1-klf8MRPHLNO
    klf8MO2-klf8MRPHLNO
    klf8MO3-klf8MRPHLNO
    klf8MO4-klf8MRPHLNO
    metMO1-metMRPHLNO
    metMO2-metMRPHLNO
    tp53MO3-tp53MRPHLNO
    1 - 7 of 7
    Show
    Fish
    Antibodies
    Name Type Antigen Genes Isotypes Host Organism
    Ab4-pvalbpolyclonal
      IgGRabbit
      1 - 1 of 1
      Show
      Orthology
      No data available
      Engineered Foreign Genes
      Marker Marker Type Name
      EGFPEFGEGFP
      1 - 1 of 1
      Show
      Mapping
      No data available