Outer segment phagocytosis by cultured retinal pigment epithelial cells requires Gas6.
The function and viability of vertebrate photoreceptors requires the daily phagocytosis of photoreceptor outer segments (OS) by the adjacent retinal pigment epithelium (RPE). We demonstrate here a critical role in this process for Gas6 and by implication one of its receptor protein tyrosine kinases (RTKs), Mertk (Mer). Gas6 specifically and selectively stimulates the phagocytosis of OS by normal cultured rat RPE cells. The magnitude of the response is dose-dependent and shows an absolute requirement for calcium. By contrast the Royal College of Surgeons (RCS) rat RPE cells, in which a mutation in the gene Mertk results in the expression of a truncated, non-functional receptor, does not respond to Gas6. These data strongly suggest that activation of Mertk by its ligand, Gas6, is the specific signaling pathway responsible for initiating the ingestion of shed OS. Moreover, photoreceptor degeneration in the RCS rat retina, which lacks Mertk, and in humans with a mutation in Mertk, strongly suggests that the Gas6/Mertk signaling pathway is essential for photoreceptor viability. We believe that this is the first demonstration of a specific function for Gas6 in the eye.
Hall
M O
MO
Jules Stein Eye Institute, UCLA Medical Center, 100 Stein Plaza, Los Angeles, CA 90095-7008, USA. hall@jsei.ucla.edu
Prieto
A L
AL
Obin
M S
MS
Abrams
T A
TA
Burgess
B L
BL
Heeb
M J
MJ
Agnew
B J
BJ
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002118:Calcium / Q000502:physiology; D018929:Cell Culture Techniques; D004305:Dose-Response Relationship, Drug; D036341:Intercellular Signaling Peptides and Proteins; D010587:Phagocytosis / Q000187:drug effects* / Q000502:physiology; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D011506:Proteins / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D011518:Proto-Oncogene Proteins; D051381:Rats; D020318:Rats, Long-Evans; D011922:Rats, Mutant Strains; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D012162:Retinal Degeneration / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012374:Rod Cell Outer Segment / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000076202:c-Mer Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D002118:Calcium; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C490765:Mertk protein, rat