PUBLICATION

Hcfc1b, a zebrafish ortholog of HCFC1, regulates craniofacial development by modulating MMACHC expression

Authors
Quintana, A.M., Geiger, E.A., Achilly, N., Rosenblatt, D.S., Maclean, K.N., Stabler, S.P., Artinger, K.B., Appel, B., Shaikh, T.H.
ID
ZDB-PUB-141005-7
Date
2014
Source
Developmental Biology   396(1): 94-106 (Journal)
Registered Authors
Appel, Bruce, Artinger, Kristin Bruk
Keywords
Cobalamin, Craniofacial defects, Facial dysmorphia, HCFC1, MMACHC
MeSH Terms
  • Humans
  • Carrier Proteins/genetics
  • Carrier Proteins/physiology*
  • Gene Knockdown Techniques
  • Cell Differentiation
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/physiology*
  • Vitamin B 12/metabolism
  • Zebrafish/genetics
  • Neural Crest/cytology
  • Neural Crest/physiology
  • Stem Cells/cytology
  • Mutation
  • Body Patterning/genetics
  • Green Fluorescent Proteins/metabolism
  • Cell Movement
  • Mice, Transgenic
  • Animals
  • Branchial Region/physiology
  • Craniofacial Abnormalities/genetics
  • Chondrocytes/cytology
  • Gene Expression Regulation, Developmental*
  • Phenotype
  • Host Cell Factor C1/genetics
  • Host Cell Factor C1/physiology*
(all 25)
PubMed
25281006 Full text @ Dev. Biol.
Abstract
Mutations in HCFC1 (MIM300019), have been recently associated with cblX (MIM309541), an X-linked, recessive disorder characterized by multiple congenital anomalies including craniofacial abnormalities. HCFC1 is a transcriptional co-regulator that modulates the expression of numerous downstream target genes including MMACHC, but it is not clear how these HCFC1 targets play a role in the clinical manifestations of cblX. To begin to elucidate the mechanism by which HCFC1 modulates disease phenotypes, we have carried out loss of function analyses in the developing zebrafish. Of the two HCFC1 orthologs in zebrafish, hcfc1a and hcfc1b, the loss of hcfc1b specifically results in defects in craniofacial development. Subsequent analysis revealed that hcfc1b regulates cranial neural crest cell differentiation and proliferation within the posterior pharyngeal arches. Further, the hcfc1b-mediated craniofacial abnormalities were rescued by expression of human MMACHC, a downstream target of HCFC1 that is aberrantly expressed in cblX. Furthermore, we tested distinct human HCFC1 mutations for their role in craniofacial development and demonstrated variable effects on MMACHC expression in humans and craniofacial development in zebrafish. Notably, several individuals with mutations in either HCFC1 or MMACHC have been reported to have mild to moderate facial dysmorphia. Thus, our data demonstrates that HCFC1 plays a role in craniofacial development, which is in part mediated through the regulation of MMACHC expression.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ba2TgTransgenic Insertion
    i106TgTransgenic Insertion
      vu234TgTransgenic Insertion
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        hcfc1aMO1-hcfc1aMRPHLNO
        hcfc1bMO1-hcfc1bMRPHLNO
        mmachcMO1-mmachcMRPHLNO
        tp53MO4-tp53MRPHLNO
        1 - 4 of 4
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        Fish
        Antibodies
        No data available
        Orthology
        No data available
        Engineered Foreign Genes
        Marker Marker Type Name
        EGFPEFGEGFP
        mRFPEFGmRFP
        RFPEFGRFP
        1 - 3 of 3
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        Mapping
        No data available