Iron-mediated retinal degeneration in haemojuvelin-knockout mice

Jaya Pranava Gnana-Prakasam, Amany Mohamed Tawfik, Michelle Romej, Sudha Ananth, Pamela Moore Martin, Sylvia B Smith, Vadivel Ganapathy

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Haemochromatosis is a genetic disorder of iron overload resulting from loss-of-function mutations in genes coding for the iron-regulatory proteins HFE (human leucocyte antigen-like protein involved in iron homoeostasis), transferrin receptor 2, ferroportin, hepcidin and HJV (haemojuvelin). Recent studies have established the expression of all of the five genes in the retina, indicating their importance in retinal iron homoeostasis. Previously, we demonstrated that HJV is expressed in RPE (retinal pigment epithelium), the outer and inner nuclear layers and the ganglion cell layer. In the present paper, we report on the consequences of Hjv deletion on the retina in mice. Hjv -/-mice at ≥18 months of age had increased iron accumulation in the retina with marked morphological damage compared with age-matched controls; these changes were not found in younger mice. The retinal phenotype in Hjv -/- mice included hyperplasia of RPE. We isolated RPE cells from wild-type and Hjv -/- mice and examined their growth patterns. Hjv -/-RPE cells were less senescent and exhibited a hyperproliferative phenotype. Hjv -/- RPE cells also showed up-regulation of Slc7a11 (solute carrier family 7 member 11 gene), which encodes the 'transporter proper' subunit xCT in the heterodimeric amino acid transporter xCT/4F2hc (cystine/glutamate exchanger). BMP6 (bone morphogenetic protein 6) could not induce hepcidin expression in Hjv -/- RPE cells, confirming that retinal cells require HJV for induction of hepcidin via BMP6 signalling. HJV is a glycosylphosphatidylinositol-anchored protein, and the membrane-associated HJV is necessary for BMP6-mediated activation of hepcidin promoter inRPE cells. Taken together, these results confirm the biological importance of HJV in the regulation of iron homoeostasis in the retina and in RPE.

Original languageEnglish (US)
Pages (from-to)599-608
Number of pages10
JournalBiochemical Journal
Volume441
Issue number2
DOIs
StatePublished - Jan 15 2012

Fingerprint

Retinal Degeneration
Retinal Pigments
Retinal Pigment Epithelium
Knockout Mice
Hepcidins
Iron
Bone Morphogenetic Protein 6
Retina
Homeostasis
Genes
Iron-Regulatory Proteins
Cells
Phenotype
Amino Acid Transport Systems
Glycosylphosphatidylinositols
Inborn Genetic Diseases
Transferrin Receptors
Iron Overload
Hemochromatosis
Cystine

Keywords

  • Bone morphogenetic protein (BMP)
  • Haemochromatosis
  • Haemojuvelin (HJV)
  • Hepcidin
  • Knockout mouse
  • Retinal pigment epithelium (RPE)

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Iron-mediated retinal degeneration in haemojuvelin-knockout mice. / Gnana-Prakasam, Jaya Pranava; Tawfik, Amany Mohamed; Romej, Michelle; Ananth, Sudha; Martin, Pamela Moore; Smith, Sylvia B; Ganapathy, Vadivel.

In: Biochemical Journal, Vol. 441, No. 2, 15.01.2012, p. 599-608.

Research output: Contribution to journalArticle

Gnana-Prakasam, Jaya Pranava ; Tawfik, Amany Mohamed ; Romej, Michelle ; Ananth, Sudha ; Martin, Pamela Moore ; Smith, Sylvia B ; Ganapathy, Vadivel. / Iron-mediated retinal degeneration in haemojuvelin-knockout mice. In: Biochemical Journal. 2012 ; Vol. 441, No. 2. pp. 599-608.
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