Reevaluation of Dystrophin Localization in the Mouse Retina

Abstract

PURPOSE. The roles of dystrophins in retinal physiology remain elusive. The lack of proper clustering of the potassium channel Kir4.1 and of the aquaporin AQP4 was proposed to be the basis of the ERG abnormality observed in many Duchenne muscular dystrophy (DMD) patients. However, the electroretinogram of Dp71-null mice, in which this clustering is disrupted, shows only a moderate reduction of the b-wave with no change in the implicit times. Additionally, the deficit in color discrimination found in DMD patients is hard to explain through the known expression of DMD gene products. The authors thus decided to reexamine their distribution in the mouse retina. METHODS. Messenger RNA distribution was assessed by PCR coupled to laser microdissection of the outer and inner nuclear layers and by in situ hybridization for Dp427. Mouse retinas were double labeled for dystrophins versus presynaptic and postsynaptic proteins or antibodies specific for Dp427 or Dp427+Dp260. RESULTS. Messengers for Dp427, Dp260, and Dp140 were present in the inner nuclear layer. Dp427 mRNA was further detected in bipolar cells and in some amacrine cells by in situ hybridization. Comparative labeling in wild-type and mdx(5Cv) retinas (lacking Dp427) indicated a differential distribution of Dp427 and Dp260 between rod and cone terminals. CONCLUSIONS. In addition to their localization in photoreceptor terminals, Dp427, Dp260, and Dp140 are expressed in inner nuclear layer neurons, notably in bipolar cells for Dp427. Dp427 was proportionally more expressed in cone- than in rod-associated synapses compared with Dp260.

Ocular and neurodevelopmental features of Duchenne muscular dystrophy: a signature of dystrophin function in the central nervous system

“…We found ERG changes corresponding with the recently reported differential expression of Dp isoforms between retinal subnetworks in animal models, with Dp427 allied more with cone pathways and Dp260 with rods. 19 We recognise now that ERG b-wave amplitude mainly depends on depolarisation of on-bipolar cells, 40 rather than potassium channels on the Müller glial cells, 41 which are altered in the Dp71-null mouse models of DMD. This explains why ERGs reported in DMD patients differ from some previously predicted DMD mouse knockout models.…”

“…Dp427, Dp260 and Dp140 are located in photoreceptor terminals, whereas Dp71 is expressed in Müller glia cells. [16][17][18][19][20] Recently, Dp427, Dp260 and Dp140 expressions have been identified in inner retinal layer neurons as well; Dp427 was expressed proportionately more at cone than rod synapses, in bipolar cells and some amacrine cells. 19 Mutations downstream of exon 30, which affect Dp260 expression, are associated with an abnormal scotopic electroretinogram (ERG) waveform [21][22][23][24] and some impairment of red-green colour vision.…”

“…[16][17][18][19][20] Recently, Dp427, Dp260 and Dp140 expressions have been identified in inner retinal layer neurons as well; Dp427 was expressed proportionately more at cone than rod synapses, in bipolar cells and some amacrine cells. 19 Mutations downstream of exon 30, which affect Dp260 expression, are associated with an abnormal scotopic electroretinogram (ERG) waveform [21][22][23][24] and some impairment of red-green colour vision. 25 In light of the recent retinal expression studies, we sought to explore the clinical ERG as a potential biomarker of CNS dystrophin expression associated with different DMD genotypes and recorded ERGs to a wide range of flash strengths in a cohort of individuals with a range of mutations across the DMD gene.…”

Asymmetrical Functional Deficits of ON and OFF Retinal Processing in the mdx3Cv Mouse Model of Duchenne Muscular Dystrophy

“…Besides Dp260, the predominant retinal gene products of dystrophin found in the outer plexiform layer (OPL), 3 the full protein Dp427, and shorter DMD gene products Dp140 and Dp71 are also found at various locations in the retina (reviewed in Ref. 4).…”

Avaliação das vias do sistema visual por eletrorretinograma e testes psicofísicos na Distrofia Muscular de Duchenne e na Diabetes Mellitus tipo 1

“…A Dp260 é mais expressa na CNE seguida da Dp140 e da Dp427. E o oposto ocorre na CNI que tem mais Dp427 expressa seguida das Dp140 e Dp260 (Wersinger et al, 2011). Estes resultados mostram que a distrofina não está restrita a retina externa, portanto pode afetar diferentes funções visuais.…”