Ectopic Norrin Induces Growth of Ocular Capillaries and Restores Normal Retinal Angiogenesis in Norrie Disease Mutant Mice

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 (Ndp

Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy

“…Mice deficient in Lrp5, Fzd4, Norrin, or Tspan12 all display similar retinal vascular phenotypes, including delayed vascular development, persistent hyaloid vasculature, lack of inner retinal vasculature, and impaired visual function. 6,17,49 Although genetic overexpression of Norrin 52,53 or stabilization of b-catenin 40 were found to be effective in rescuing vascular defects in Norrin-deficient mice, no pharmacologic treatments have yet been identified for FEVR or Norrie disease. Future investigations will determine whether lithium treatment is also effective in genetic models of FEVR other than Lrp5 À/À mice.…”

Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP

“…Moreover, the Ndph knockout mice developed severe structural irregularities of the retinal vascular system formation. The hyaloid blood vessels delayed to regress [Luhmann et al, 2005;Ohlmann et al, 2005;Richter et al, 1998], and both superficial and intraretinal vasculature was severely impaired because a large number of blood vessels or capillaries was defective or even absent. The lack of normal blood supply that nourishes the different retinal cell layers results in local hypoxic conditions, especially in the inner retina.…”

“…Defects in the cochlear stria vascularis of Ndph y/À animals resulted in progressive hearing loss, leading to deafness, similar to the human phenotype [Rehm et al, 2002]. Adding to that, more light was shed on the biochemical role of NDP by overexpressing it transgenically in the eyes of Ndph y/À mice under the control of a lens-specific promoter [Ohlmann et al, 2005]. Ectopically expressed Norrin surprisingly restored the normal retinal vasculature, while respecting the normal local architecture of the blood vessels.…”

Norrin Promotes Vascular Regrowth after Oxygen-Induced Retinal Vessel Loss and Suppresses Retinopathy in Mice

“…In at least one-third of the cases, Norrie disease is accompanied by sensorineural deafness and mental retardation. Mutant mice with a targeted disruption of Ndp (Ndp y /Ϫ ) show a lack of the primary vasculature in the retinal periphery, a complete absence of intraretinal capillaries and a progressive loss of vessels within the stria vascularis of the cochlea (Richter et al, 1998;Rehm et al, 2002;Luhmann et al, 2005b;Ohlmann et al, 2005). The structural changes correlate with a marked loss of function, as mutant Ndp y /Ϫ mice develop blindness (Ruether et al, 1997) and sensorineural deafness (Rehm et al, 2002).…”

“…The structural changes correlate with a marked loss of function, as mutant Ndp y /Ϫ mice develop blindness (Ruether et al, 1997) and sensorineural deafness (Rehm et al, 2002). The vascular phenotype of Ndp (y /Ϫ) mutant animals is completely rescued in mixed ␤B1-Crystallin-Norrin/Ndp (y /Ϫ) mice with transgenic overexpression of ectopic Norrin under control of a lens-specific ␤B1-Crystallin promoter fragment (Ohlmann et al, 2005). Norrin shows selective and high-affinity binding to the frizzled-4 receptor (Fzd4) and induces activation of the classical Wnt/␤-catenin signaling pathway (Xu et al, 2004).…”