title: Bone spicule pigment formation in retinitis pigmentosa: insights from a mouse model.
abstract: BACKGROUND
  Bone spicule pigments (BSP) are a hallmark of retinitis pigmentosa (RP). In this study, we examined the process of BSP formation in the rhodopsin knockout (rho (-/-)) mouse, a murine model for human RP.
  
  
  METHODS
  In rho (-/-) mice from 2 to 16 months of age, representing the range from early to late stages of degeneration, retinal sections and whole mounts were examined morphologically by light and electron microscopy. The results were compared to scanning laser ophthalmoscopy of BSP degeneration in human RP.
  
  
  RESULTS
  After the loss of all photoreceptor cells in rho-/- mice, the outer retina successively degenerated, leading to approximation and finally a direct contact of inner retinal vessels and the retinal pigment epithelium (RPE). We could show that it was the event of proximity of retinal vessel and RPE that triggered migration of RPE cells along the contacting vessels towards the inner retina. Ultrastructurally, these mislocalized RPE cells partially sealed the vessels by tight junction linkage and deposited extracellular matrix perivascularly. Also, the vascular endothelium developed fenestrations similar to the RPE-choroid interface. In whole mounts, the pigmented cell clusters outlining retinal capillaries correlated well with BSPs in human RP. The structure of the inner retina remained well preserved, even in late stages.
  
  
  CONCLUSIONS
  The Rho (-/-) mouse is the first animal model that depicts all major pathological changes, even in the late stages of RP. Using the rho (-/-) mouse model we were able to analyze the complete dynamic process of BSP formation. Therefore we conclude that: (1) In rho (-/-) retinas, BSPs only form in areas devoid of photoreceptors; (2) Direct contact between inner retinal vessels and RPE appears to be a major trigger for migration of RPE cells; (3) The distribution of the RPE cells in BSPs reflects the vascular network at the time of formation. The similarity of the disease process between mouse and human and the possibility to study all consecutive steps of the course of the disease makes the rho (-/-) mouse valuable for further insights in the dynamics of BSP formation in human RP.
authors.affiliation: University Eye Hospital Tuebingen, Centre for Ophthalmology, Schleichstr. 12, 72076, Tuebingen, Germany. gesine.jaissle@googlemail.com
authors.forename: Gesine B
authors.initials: GB
authors.lastname: Jaissle
authors.forename: Christian Albrecht
authors.initials: CA
authors.lastname: May
authors.forename: Serge A
authors.initials: SA
authors.lastname: van de Pavert
authors.forename: Andreas
authors.initials: A
authors.lastname: Wenzel
authors.forename: Ellen
authors.initials: E
authors.lastname: Claes-May
authors.forename: Andreas
authors.initials: A
authors.lastname: Giessl
authors.forename: Peter
authors.initials: P
authors.lastname: Szurman
authors.forename: Uwe
authors.initials: U
authors.lastname: Wolfrum
authors.forename: Jan
authors.initials: J
authors.lastname: Wijnholds
authors.forename: M D
authors.initials: MD
authors.lastname: Fischer
authors.forename: M D
authors.initials: MD
authors.lastname: Fisher
authors.forename: P
authors.initials: P
authors.lastname: Humphries
authors.forename: M W
authors.initials: MW
authors.lastname: Seeliger
mesh_terms: D000818:Animals; D002465:Cell Movement; D004195:Disease Models, Animal; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000648:ultrastructure*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000648:ultrastructure; D012171:Retinal Vessels / Q000378:metabolism / Q000648:ultrastructure; D012174:Retinitis Pigmentosa / Q000378:metabolism / Q000473:pathology*; D012243:Rhodopsin / Q000235:genetics; D041623:Tomography, Optical Coherence
chemical_list: C498441:Bsn protein, mouse; D009419:Nerve Tissue Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012243:Rhodopsin