Differential gene expression in Ndph-knockout mice in retinal development.
OBJECTIVE
Mutations in the NDP gene impair angiogenesis in the eyes of patients diagnosed with a type of blindness belonging to the group of exudative vitreoretinopathies. This study was conducted to investigate the differential gene expression caused by the absence of Norrin (the NDP protein) in the developing mouse retina and to elucidate early pathogenic events.


METHODS
A comparative gene expression analysis was performed on postnatal day (p)7 retinas from a knockout mouse model for Norrie disease using gene microarrays. Subsequently, results were verified by quantitative real-time PCR analyses. Immunohistochemistry was performed for the vascular permeability marker plasmalemma vesicle associated protein (Plvap).


RESULTS
Our study identified expression differences in Ndph(y/-) versus wild-type mice retinas at p7. Gene transcription of the neutral amino acid transporter Slc38a5, apolipoprotein D (ApoD), and angiotensin II receptor-like 1 (Agtrl1) was decreased in the knockout mouse, whereas transcript levels of adrenomedullin (Adm) and of the plasmalemma vesicle associated protein (Plvap) were increased in comparison to the wild-type. In addition, ectopic expression of Plvap was found in the developing retinal vasculature of Norrin-knockout mice on the protein level.


CONCLUSIONS
These data provide molecular evidence for a role of Norrin in the development of the retinal vasculature. Expression of two genes, Plvap and Slc38a5, is considerably altered in retinal development of Norrin-knockout mice and may reflect or contribute to the pathogenesis of the disease. In particular, ectopic expression of Plvap is consistent with hallmark disease symptoms in mice and humans.
Schäfer
Nikolaus F
NF
Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland.
Luhmann
Ulrich F O
UF
Feil
Silke
S
Berger
Wolfgang
W
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism; D000818:Animals; D053399:Apolipoproteins D / Q000235:genetics / Q000378:metabolism; D002199:Capillary Permeability; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics*; D019084:Fluorescent Antibody Technique, Indirect; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D015861:Retinal Neovascularization / Q000235:genetics* / Q000378:metabolism; D012171:Retinal Vessels / Q000254:growth & development* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051153:Wnt Proteins / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; D026921:Amino Acid Transport Systems, Neutral; D053399:Apolipoproteins D; D002352:Carrier Proteins; D005136:Eye Proteins; D008565:Membrane Proteins; C489916:Ndph protein, mouse; D009419:Nerve Tissue Proteins; C486772:Plvap protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin