Ectopic Norrin induces growth of ocular capillaries and restores normal retinal angiogenesis in Norrie disease mutant mice

Andreas Ohlmann, Michael Scholz, Andreas Goldwich, Bharesh K. Chauhan, Kristiane Hudl, Anne V. Ohlmann, Eberhart Zrenner, Wolfgang Berger, Ales Cvekl, Mathias W. Seeliger, Ernst R. Tamm

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Norrie disease is an X-linked retinal dysplasia that presents with congenital blindness, sensorineural deafness, and mental retardation. Norrin, the protein product of the Norrie disease gene (NDP), is a secreted protein of unknown biochemical function. Norrie disease (Ndpy/-) mutant mice that are deficient in norrin develop blindness, show a distinct failure in retinal angiogenesis, and completely lack the deep capillary layers of the retina. We show here that the transgenic expression of ectopic norrin under control of a lens-specific promoter restores the formation of a normal retinal vascular network in Ndpy/- mutant mice. The improvement in structure correlates with restoration of neuronal function in the retina. In addition, lenses of transgenic mice with ectopic expression of norrin show significantly more capillaries in the hyaloid vasculature that surrounds the lens during development. In vitro, lenses of transgenic mice in coculture with microvascular endothelial cells induce proliferation of the cells. Transgenic mice with ectopic expression of norrin show more bromodeoxyuridine-labeled retinal progenitor cells at embryonic day 14.5 and thicker retinas at postnatal life than wild-type littermates, indicating a putative direct neurotrophic effect of norrin. These data provide direct evidence that norrin induces growth of ocular capillaries and that pharmacologic modulation of norrin might be used for treatment of the vascular abnormalities associated with Norrie disease or other vascular disorders of the retina.

Original languageEnglish (US)
Pages (from-to)1701-1710
Number of pages10
JournalJournal of Neuroscience
Volume25
Issue number7
DOIs
StatePublished - Feb 16 2005

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Lenses
Retina
Transgenic Mice
Growth
Blood Vessels
Retinal Dysplasia
Deaf-Blind Disorders
Retinal Vessels
Bromodeoxyuridine
Blindness
Coculture Techniques
Intellectual Disability
Proteins
Stem Cells
Endothelial Cells
Cell Proliferation
Norrie disease
Genes
Ectopic Gene Expression

Keywords

  • Angiogenesis
  • Frizzled 4
  • Norrie disease
  • PIGF
  • Retina
  • VEGF

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Ectopic Norrin induces growth of ocular capillaries and restores normal retinal angiogenesis in Norrie disease mutant mice. / Ohlmann, Andreas; Scholz, Michael; Goldwich, Andreas; Chauhan, Bharesh K.; Hudl, Kristiane; Ohlmann, Anne V.; Zrenner, Eberhart; Berger, Wolfgang; Cvekl, Ales; Seeliger, Mathias W.; Tamm, Ernst R.

In: Journal of Neuroscience, Vol. 25, No. 7, 16.02.2005, p. 1701-1710.

Research output: Contribution to journalArticle

Ohlmann, A, Scholz, M, Goldwich, A, Chauhan, BK, Hudl, K, Ohlmann, AV, Zrenner, E, Berger, W, Cvekl, A, Seeliger, MW & Tamm, ER 2005, 'Ectopic Norrin induces growth of ocular capillaries and restores normal retinal angiogenesis in Norrie disease mutant mice', Journal of Neuroscience, vol. 25, no. 7, pp. 1701-1710. https://doi.org/10.1523/JNEUROSCI.4756-04.2005
Ohlmann, Andreas ; Scholz, Michael ; Goldwich, Andreas ; Chauhan, Bharesh K. ; Hudl, Kristiane ; Ohlmann, Anne V. ; Zrenner, Eberhart ; Berger, Wolfgang ; Cvekl, Ales ; Seeliger, Mathias W. ; Tamm, Ernst R. / Ectopic Norrin induces growth of ocular capillaries and restores normal retinal angiogenesis in Norrie disease mutant mice. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 7. pp. 1701-1710.
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