PUBLICATION

A zebrafish model of Poikiloderma with Neutropenia recapitulates the human syndrome hallmarks and traces back neutropenia to the myeloid progenitor

Authors
Colombo, E.A., Carra, S., Fontana, L., Bresciani, E., Cotelli, F., Larizza, L.
ID
ZDB-PUB-151103-3
Date
2015
Source
Scientific Reports   5: 15814 (Journal)
Registered Authors
Bresciani, Erica, Cotelli, Franco
Keywords
Disease model, Diseases, Medical genetics
MeSH Terms
  • Skin Diseases/genetics
  • Skin Diseases/metabolism
  • Stem Cells/metabolism*
  • Humans
  • Zebrafish/genetics*
  • Myeloid Cells/metabolism*
  • Neutropenia/genetics*
  • Down-Regulation/genetics
  • Skin Abnormalities/genetics*
  • Morpholinos/genetics
  • Phenotype
  • RNA Splicing/genetics
  • RNA, Small Nuclear/genetics
  • Animals
(all 14)
PubMed
26522474 Full text @ Sci. Rep.
Abstract
Poikiloderma with Neutropenia (PN) is an autosomal recessive genodermatosis characterized by early-onset poikiloderma, pachyonychia, hyperkeratosis, bone anomalies and neutropenia, predisposing to myelodysplasia. The causative C16orf57/USB1 gene encodes a conserved phosphodiesterase that regulates the stability of spliceosomal U6-RNA. The involvement of USB1 in splicing has not yet allowed to unveil the pathogenesis of PN and how the gene defects impact on skin and bone tissues besides than on the haematological compartment. We established a zebrafish model of PN using a morpholino-knockdown approach with two different splicing morpholinos. Both usb1-depleted embryos displayed developmental abnormalities recapitulating the signs of the human syndrome. Besides the pigmentation and osteochondral defects, usb1-knockdown caused defects in circulation, manifested by a reduced number of circulating cells. The overall morphant phenotype was also obtained by co-injecting sub-phenotypic dosages of the two morpholinos and could be rescued by human USB1 RNA. Integrated in situ and real-time expression analyses of stage-specific markers highlighted defects of primitive haematopoiesis and traced back the dramatic reduction in neutrophil myeloperoxidase to the myeloid progenitors showing down-regulated pu.1 expression. Our vertebrate model of PN demonstrates the intrinsic requirement of usb1 in haematopoiesis and highlights PN as a disorder of myeloid progenitors associated with bone marrow dysfunction.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
i114TgTransgenic Insertion
    nz50TgTransgenic Insertion
      s843TgTransgenic Insertion
        sd2TgTransgenic Insertion
          1 - 4 of 4
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          Human Disease / Model
          Sequence Targeting Reagents
          Target Reagent Reagent Type
          tp53MO4-tp53MRPHLNO
          usb1MO3-usb1MRPHLNO
          usb1MO4-usb1MRPHLNO
          1 - 3 of 3
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          Fish
          Antibodies
          No data available
          Orthology
          Gene Orthology
          usb1
          1 - 1 of 1
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          Engineered Foreign Genes
          Marker Marker Type Name
          DsRedEFGDsRed
          DsRed2EFGDsRed2
          EGFPEFGEGFP
          GFPEFGGFP
          1 - 4 of 4
          Show
          Mapping
          No data available