An RCS-like retinal dystrophy phenotype in mer knockout mice.
OBJECTIVE
To determine whether mice that are homozygous for a targeted disruption of the Mer receptor tyrosine kinase gene (mer(kd)) manifest a retinal dystrophy phenotype similar to RCS rats, which carry a mutation in the orthologous gene MERTK:


METHODS
Eyes of mer(kd) and C57BL/6 wild-type (WT) mice were examined by light and electron microscopy, whole-eye rhodopsin measurement, and Ganzfeld electroretinography (ERG).


RESULTS
The mer(kd) mice showed rapid, progressive degeneration of the photoreceptors (PRs). Features of the phenotype common to mer(kd) mice and RCS rats included the absence or near absence of phagosomes in the retinal pigment epithelium (RPE) at the peak of outer segment (OS) disc shedding, accumulation of debris and whorls of membranes at the RPE-OS interface, transient supernormal rhodopsin content and OS lengths, the presence of OS vacuoles beginning at early ages, and a relatively slow removal of pyknotic PR nuclei. Most PRs were missing, and OS debris was removed by approximately postnatal day (P)45. Scotopic ERG responses were lower than age-matched WT responses and declined with PR loss. Photopic responses were preserved better than scotopic responses, corresponding with preferential cone preservation as judged histologically. ERG amplitudes were usually unmeasurable beyond P40, although a small-amplitude scotopic threshold response (STR) could still be elicited at P253 in some mice when only scattered PR nuclei remained.


CONCLUSIONS
Ablation of Mer function in mer(kd) mice results in a retinal phenotype almost identical with that of RCS rats. The similarity in phenotypes between the two rodent models suggests that an RPE phagocytic defect is a feature of all types of retinal degeneration caused by loss of function of Mer tyrosine kinase, perhaps including mutations in human MERTK.
Duncan
Jacque L
JL
Department of Ophthalmology, Beckman Vision Center, University of California, San Francisco, California 94143, USA.
LaVail
Matthew M
MM
Yasumura
Douglas
D
Matthes
Michael T
MT
Yang
Haidong
H
Trautmann
Nikolaus
N
Chappelow
Aimee V
AV
Feng
Wei
W
Earp
H Shelton
HS
Matsushima
Glenn K
GK
Vollrath
Douglas
D
D000818:Animals; D004596:Electroretinography; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis; D010588:Phagosomes / Q000473:pathology; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D012160:Retina / Q000201:enzymology / Q000648:ultrastructure*; D012162:Retinal Degeneration / Q000201:enzymology* / Q000473:pathology*; D012243:Rhodopsin / Q000378:metabolism; D000076202:c-Mer Tyrosine Kinase
D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012243:Rhodopsin; C490767:Mertk protein, mouse; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase