A retinal neuronal developmental wave of retinoschisin expression begins in ganglion cells during layer formation.
OBJECTIVE
Mutations in the retinoschisin gene, RS-1, cause juvenile X-linked retinoschisis (XLRS), a dystrophy characterized by delamination of the inner retinal layers, leading to visual impairment. Although the retinoschisin protein (RS) is expressed most abundantly in photoreceptors in the outer retina, XLRS disease affects the innermost retinal layers, including the nerve fiber layer that contains retinal ganglion cells (RGCs). Considering the histopathological and electrophysiological characteristics of the clinical disease, the present study was conducted to evaluate the local cellular expression of RS-1 during retinal development.


METHODS
RS protein and RS-1 mRNA were localized to specific retinal cell types in embryonic to adult mice by immunohistochemistry, confocal immunofluorescence microscopy, catalyzed reporter deposition in situ hybridization, and laser capture microdissection/RT-PCR.


RESULTS
RS-1 mRNA was expressed first in RGCs by postnatal day (P)1, after terminal differentiation. Expression then moved posteriorly through the retina in a spatial and temporal developmental wave, as additional neuronal classes were born and synaptic layers were formed. RS was expressed by bipolar cells at a time when these neurons were establishing functional synapses with photoreceptors, evidenced by the appearance of the electroretinogram b-wave between P12 and P14.


CONCLUSIONS
All major classes of adult retinal neurons, with the possible exception of horizontal cells, express RS protein and mRNA, strongly suggesting that retinoschisin in the inner retina is synthesized locally rather than being transported, as earlier proposed, from distal retinal photoreceptors. Continued expression of RS by mature inner-retinal neurons supports the possibility of a therapeutic strategy of protein replacement to treat both infants and adults with XLRS.
National Institute on Deafness and Other Communication Disorders, Bethesda, Maryland 20892, USA.
Yuichiro
Y
Takada
Robert N
RN
Fariss
Atsuhiro
A
Tanikawa
Yong
Y
Zeng
Deborah
D
Carper
Ronald
R
Bush
Paul A
PA
Sieving
D000375:Aging / Q000378:metabolism; D000818:Animals; D004622:Embryo, Mammalian / Q000473:pathology / Q000503:physiopathology; D005314:Embryonic and Fetal Development; D005136:Eye Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000196:embryology* / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000473:pathology; D041441:Retinoschisis / Q000196:embryology* / Q000473:pathology; D013569:Synapses; D014018:Tissue Distribution
D005136:Eye Proteins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; C108726:RS1 protein, human