PUBLICATION
Zebrafish Klf4 maintains the ionocyte progenitor population by regulating epidermal stem cell proliferation and lateral inhibition
- Authors
- Chen, Y.C., Liao, B.K., Lu, Y.F., Liu, Y.H., Hsieh, F.C., Hwang, P.P., Hwang, S.L.
- ID
- ZDB-PUB-190402-19
- Date
- 2019
- Source
- PLoS Genetics 15: e1008058 (Journal)
- Registered Authors
- Hwang, Pung Pung, Hwang, Sheng-Ping L.
- Keywords
- none
- MeSH Terms
-
- Promoter Regions, Genetic
- Cell Proliferation
- Cyclin-Dependent Kinase Inhibitor p21/genetics
- Cyclin-Dependent Kinase Inhibitor p21/metabolism
- Receptors, Notch/genetics
- Receptors, Notch/metabolism
- Zebrafish/embryology*
- Zebrafish/genetics
- Zebrafish/metabolism*
- Gene Expression Regulation, Developmental
- Embryonic Stem Cells/cytology*
- Embryonic Stem Cells/metabolism*
- Animals
- Animals, Genetically Modified
- Amino Acid Sequence
- Gills/cytology
- Gills/embryology
- Gills/metabolism
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Ectoderm/cytology
- Ectoderm/embryology
- Ectoderm/metabolism
- Trans-Activators/genetics
- Trans-Activators/metabolism
- Cell Differentiation
- Zebrafish Proteins/deficiency
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- Body Patterning
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
- Epidermal Cells/cytology*
- Epidermal Cells/metabolism*
- Kruppel-Like Transcription Factors/deficiency
- Kruppel-Like Transcription Factors/genetics
- Kruppel-Like Transcription Factors/metabolism*
- Phosphoproteins/genetics
- Phosphoproteins/metabolism
- Ion Transport
- PubMed
- 30933982 Full text @ PLoS Genet.
Citation
Chen, Y.C., Liao, B.K., Lu, Y.F., Liu, Y.H., Hsieh, F.C., Hwang, P.P., Hwang, S.L. (2019) Zebrafish Klf4 maintains the ionocyte progenitor population by regulating epidermal stem cell proliferation and lateral inhibition. PLoS Genetics. 15:e1008058.
Abstract
In the skin and gill epidermis of fish, ionocytes develop alongside keratinocytes and maintain body fluid ionic homeostasis that is essential for adaptation to environmental fluctuations. It is known that ionocyte progenitors in zebrafish embryos are specified from p63+ epidermal stem cells through a patterning process involving DeltaC (Dlc)-Notch-mediated lateral inhibition, which selects scattered dlc+ cells into the ionocyte progenitor fate. However, mechanisms by which the ionocyte progenitor population is modulated remain unclear. Krüppel-like factor 4 (Klf4) transcription factor was previously implicated in the terminal differentiation of mammalian skin epidermis and is known for its bifunctional regulation of cell proliferation in a tissue context-dependent manner. Here, we report novel roles for zebrafish Klf4 in the ventral ectoderm during embryonic skin development. We found that Klf4 was expressed in p63+ epidermal stem cells of the ventral ectoderm from 90% epiboly onward. Knockdown or knockout of klf4 expression reduced the proliferation rate of p63+ stem cells, resulting in decreased numbers of p63+ stem cells, dlc-p63+ keratinocyte progenitors and dlc+ p63+ ionocyte progenitor cells. These reductions subsequently led to diminished keratinocyte and ionocyte densities and resulted from upregulation of the well-known cell cycle regulators, p53 and cdkn1a/p21. Moreover, mutation analyses of the KLF motif in the dlc promoter, combined with VP16-klf4 or engrailed-klf4 mRNA overexpression analyses, showed that Klf4 can bind the dlc promoter and modulate lateral inhibition by directly repressing dlc expression. This idea was further supported by observing the lateral inhibition outcomes in klf4-overexpressing or knockdown embryos. Overall, our experiments delineate novel roles for zebrafish Klf4 in regulating the ionocyte progenitor population throughout early stem cell stage to initiation of terminal differentiation, which is dependent on Dlc-Notch-mediated lateral inhibition.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping