Severe retinal degeneration associated with disruption of semaphorin 4A.
OBJECTIVE
Semaphorin 4A (Sema4A) is a member of the transmembrane class 4 family of semaphorins. It has recently been shown to participate in cell-cell communication in the immune system. High levels of sema4A are also present in brain and eye, but its function in the central nervous system has not been studied. To investigate the function of Sema4A, we generated mice deficient in this transmembrane signaling molecule.


METHODS
An embryonic stem (ES) cell clone with a retroviral gene-trap insertion in the sema4A gene was used to generate mice lacking this transmembrane semaphorin. Fundus photography, fluorescein angiography, and electroretinography were used to evaluate retinal anatomy and physiology in mice lacking Sema4A. Electron microscopy and immunohistochemistry with cell-type-specific markers were used to characterize retinal development. In situ hybridization with sema4A-specific riboprobes was used to localize expression of this gene in the developing and adult eye.


RESULTS
Fundus photography performed at 14 weeks of age revealed severe retinal degeneration, attenuated retinal vessels, and depigmentation in mice lacking Sema4A. At this age, the outer nuclear layer was reduced to a single row of photoreceptor cells, and the outer plexiform layer was thin and disorganized. Disruption of Sema4A also compromised the physiological function of both rod and cone photoreceptors. Developmental studies in Sema4A-deficient mice revealed abnormal morphology of photoreceptor outer segments during the time at which they establish contacts with apical microvilli of the retinal pigment epithelium (RPE). Sema4A is expressed in the inner retina and RPE during the time at which photoreceptor outer segments elongate.


CONCLUSIONS
These findings identify a previously unknown function of Sema4A in the developing visual system and provide a useful model for understanding cell-cell interactions that occur between photoreceptors and the RPE.
Rice
Dennis S
DS
Lexicon Genetics Inc., The Woodlands, Texas 77381, USA. drice@lexgen.com
Huang
Wenhu
W
Jones
Holly A
HA
Hansen
Gwenn
G
Ye
Gui-Lan
GL
Xu
Nianha
N
Wilson
Elizabeth A
EA
Troughton
Kathy
K
Vaddi
Kris
K
Newton
Robert C
RC
Zambrowicz
Brian P
BP
Sands
Arthur T
AT
D000818:Animals; D002450:Cell Communication; D004596:Electroretinography; D005451:Fluorescein Angiography; D019084:Fluorescent Antibody Technique, Indirect; D017353:Gene Deletion; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D020419:Photoreceptor Cells, Vertebrate / Q000502:physiology* / Q000648:ultrastructure; D010857:Pigment Epithelium of Eye / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000378:metabolism / Q000503:physiopathology*; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology; D012171:Retinal Vessels / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D039961:Semaphorins / Q000172:deficiency / Q000502:physiology*
D039961:Semaphorins