EFFECTS OF MULLER CELL DISRUPTION ON MOUSE PHOTORECEPTOR CELL-DEVELOPMENT

Muller cells have been proposed to play an important role in photorece ptor cell development during the final stages of retinal maturation. T he effect of disrupting Muller cells during mouse retinal development was investigated using the specific glial cell toxin, DL-alpha-aminoad ipic acid (AAA). By giving multiple systemic injections over several d ays, impairment of Muller cell function was maintained during the peri od of photoreceptor migration and differentiation. Following three con secutive days of AAA treatment [commencing on post-natal (P) day 3, 5, 7 or 9, and examined at P8-P14], clumps of photoreceptor nuclei were displaced through the inner segments, lying immediately beneath the re tinal pigment epithelium (RPE). Apart from the scalloped appearance of the outer retina, the overall lamination pattern of the retina was re latively well preserved, Even when AAA treatment commenced as early as P3, several days prior to the formation of the outer nuclear layer, t he majority of photoreceptors migrated to their correct position and f ormed inner and outer segments. Therefore, the signals for photorecept or migration are either provided by the Muller cells prior to P3, or, alternatively, are derived from different intrinsic or extrinsic cues. Disruption of Muller cell function was evidenced by decreased glutami ne synthetase activity as well as by increased glial fibrillary acidic protein (GFAP) and decreased cellular retinaldehyde-binding protein ( CRALBP) immunoreactivity. Immunocytochemistry with an antibody to CD44 , which labels the microvilli of Muller cells at the outer limiting me mbrane, coupled with electron microscopic analysis, demonstrated that the zonulae adherentes between Muller cells and photoreceptors were ei ther irregular or absent in areas adjacent to displaced clumps of phot oreceptors. Thus AAA treatment of early post-natal mice results in loc alized disruption of the contacts between Muller cells and photorecept ors. These pathologic changes persist into adulthood since at P28, whi le short stretches of photoreceptors appeared relatively normal with f ully developed outer segments, periodic clumps of displaced photorecep tor nuclei were still present adjacent to the RPE. In conclusion, Mull er cell processes at the outer limiting membrane appear to play a crit ical role in providing a barrier to aberrant photoreceptor migration i nto the subretinal space. (C) 1995 Academic Press Limited