The Role Of Müller Cell Depletion In Retinal Degeneration?
    By Jennifer Wong | January 28th 2013 09:19 PM | Print | E-mail | Track Comments
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    Macular teleangiectasia (MacTel) is a progressive idiopathic form of retinal degeneration that occurs in adulthood, and is caused by a number of factors including diabetic retinopathy, hypertension, venous occlusion, inflammatory diseases, and blood disorders (Yannuzzi et al., 2006) (Shen et al J Neurosci 32:15715-15727).

    MacTel causes blindness through the progressive loss of photoreceptors (Ooto et al., 2011); a pathology that is associated with the local (type 1) or widespread (type 2) vascular aberrations in the retina.  These vascular aberrations include vascular dilation, leakages or breaches in the blood retina barrier (BRB), as well as subretinal neovascularization and scarring (Yannuzzi et al., 2006).

    Another clinical feature of MacTel is the profound dysfunction of the retinal pigment epithelium (RPE); a feature characterized by the loss of macular pigment, subretinal plaque accumulation, and clumping of the RPE (Cherepanoff et al., 2012) 

     Although the precise mechanism behind retinal degeneration is unclear, recent studies suggest that the answer lies in a yet unappreciated cellular player in this disorder: the Müller cell. Müller cells are retinal glial cells that span the entire thickness of the retina, and provide homeostatic support, neuroprotection, and excitability modulation for individual retinal neurons and photoreceptors (Bringmann et al., 2006).

    Müller cells can also regulate the dilation and neovascularization of the retinal vasculature, and play an important role in maintaining integrity of the BRB (Bringmann et al., 2006). 

    Although the onset of retinal degeneration is thought to be associated with Müller cell depletion (Bringmann et al., 2006; Shen et al., 2012), the role of Müller cell dysfunction in the onset of MacTel remains to be functionally established.  In the present study by Shen et al. (2012), published in the Journal of Neuroscience, the authors demonstrated the first in vivo evidence supporting the primary role of Müller cell depletion in the onset of retinal degeneration similar to MacTel and diabetic retinopathy (Shen et al., 2012).

    In this study, the authors engineered a transgenic mouse model that supports the targeted ablation of Müller cells, allowing the authors to mimic the loss of Müller cells observed at the onset of MacTel type 2 and diabetic retinopathy. The mouse model was generated by crossing a RTBP1-CreER mouse with a Rosa-DTA176, producing a RTBP1-CreER-TG mouse that expresses an attenuated DTA176 toxin (diphtheria toxin fragment A) under the control of a Müller cell-specific RTBP1 promoter (retinaldehyde binding protein 1 promoter).

    The expression of the DTA176 toxin renders Müller glia susceptible to tamoxifen (TMX), targeting Müller cells for ablation with TMX treatment. 

    Using this model, the authors confirmed that TMX treatment caused profound and specific ablation of Müller cells in the retina of RTBP1-CreER-TG  mice, and concomitant retinal pathology that strongly mimics the photoreceptor injuries  and vascular aberrations characteristic of MacTel type 2.

    Briefly, the authors observed a profound loss of photoreceptors in the retinal ultrastructure of TMX-treated RTBP1-CreER-TG mice, and the associated decline in the retina’s electrophysiological response to light. The loss of photoreceptors was correlated with aberrations in the retinal blood vessels of these mice. Vascular staining revealed profound vasodilation and tortuosity at as few as 7 days post-TMX treatment, and evidence of deep retinal neovascularization at 2 months post-TMX treatment.

    Further BRB permeability studies revealed widespread vascular leakages at 12 days post-TMX treatment, indicative of breaches in the BRB. Importantly, the observed effects of TMX in RTBP1-CreER-TG mice were not seen in wildtype mice, indicating that retinal degeneration was not caused by TMX treatment. To eliminate the possibility that the observed retinal degeneration could be caused by the bystander effect of DTA176 on neighboring retinal cells, the authors demonstrated that proteins extracted from the retinas of TMX-treated RTBP1-CreER-TG mice failed to induce retinal damage when injected into the retinas of wildtype mice.  

    Lastly, the authors were able to correlate the loss of Müller- cell-derived factors (ex: ciliary neurotrophic factor (CNTF) and pigment epithelial derived factor (PEDF)) with the retinal pathology in TMX-treated RTBP1-CreER-TG mice. Indeed, CNTF restoration and PEDF mimicry (in the form of VEGF inhibition) in RTBP1-CreER-TG mice can improve photoreceptor survival and BRB integrity following TMX treatment.

    The elegant study by Shen et al. (2012) provides the much needed functional data to support the unappreciated role of Müller cell depletion in retinal degeneration. However, this paper still falls short in defining the precise role of Müller cell depletion in the pathology of retinal disorders like MacTel. Given the important role of Müller cells in maintaining a healthy retina(Bringmann et al., 2006), it is not surprising that the ablation of Müller cells will cause widespread retinal damage. It still remains unclear whether Müller cell depletion is a primary cause of retinal degeneration, or a secondary event during the onset of retinal degeneration.

    Indeed, in a recent MacTel clinical study across 23 centers in seven countries, it was found that MacTel is associated with gene expression alterations affecting the retinal vasculature, retinal pigment epithelium (RPE), and Müller cells (Parmalee et al., 2010). It is very possible that the retinal degeneration in MacTel can be triggered by the collective molecular changes in the integral cellular and vascular components of the retina. For instance, since MacTel-associated transcriptional alterations in the retinal vasculature are found to be associated with diabetes and hypertension (both idiopathic causes of MacTel), it is very likely that vascular aberrations could be the cause of photoreceptor and Müller cell degeneration observed in MacTel (Parmalee et al., 2010).

    Likewise, it was also shown that RPE ablation can cause profound photoreceptor degeneration and Müller cell alterations, suggesting that RPE aberration may also be another unappreciated player in retinal degeneration (Longbottom et al., 2009). Collectively, these studies suggest a possibility that Müller cell depletion could simply be a pathological aftermath of the transcriptional alterations affecting the retinal vasculature, RPE, and even Müller cells, in the diseased retina.

    In light of all these possibilities, one must be careful with interpreting the results by Shen et al. (2012). Indeed, a more comprehensive mechanistic elucidation of MacTel pathology may be required to understand precisely how Müller cell depletion fits in the overall pathology of this disease. A potential strategy may be to use the targeted Cre-loxP approach, presented by Shen et al (2012), to explore how MacTel-associated transcriptional alterations (Parmalee et al., 2010) affect the complex cell biology of the retina, and ultimately contribute to the onset of retinal degeneration.

    Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov SN, Osborne NN, Reichenbach A (2006) Muller cells in the healthy and diseased retina. Prog Retin Eye Res 25:397-424.

    Cherepanoff S, Killingsworth MC, Zhu M, Nolan T, Hunyor AP, Young SH, Hageman GS, Gillies MC (2012) Ultrastructural and clinical evidence of subretinal debris accumulation in type 2 macular telangiectasia. Br J Ophthalmol 96:1404-1409.

    Longbottom R, Fruttiger M, Douglas RH, Martinez-Barbera JP, Greenwood J, Moss SE (2009) Genetic ablation of retinal pigment epithelial cells reveals the adaptive response of the epithelium and impact on photoreceptors. Proc Natl Acad Sci U S A 106:18728-18733.

    Ooto S, Hangai M, Takayama K, Sakamoto A, Tsujikawa A, Oshima S, Inoue T, Yoshimura N (2011) High-resolution imaging of the photoreceptor layer in epiretinal membrane using adaptive optics scanning laser ophthalmoscopy. Ophthalmology 118:873-881.

    Parmalee NL, Schubert C, Merriam JE, Allikmets K, Bird AC, Gillies MC, Peto T, Figueroa M, Friedlander M, Fruttiger M, Greenwood J, Moss SE, Smith LE, Toomes C, Inglehearn CF, Allikmets R (2010) Analysis of candidate genes for macular telangiectasia type 2. Mol Vis 16:2718-2726.

    Shen W, Fruttiger M, Zhu L, Chung SH, Barnett NL, Kirk JK, Lee S, Coorey NJ, Killingsworth M, Sherman LS, Gillies MC (2012) Conditional Muller Cell Ablation Causes Independent Neuronal and Vascular Pathologies in a Novel Transgenic Model. J Neurosci 32:15715-15727.

    Yannuzzi LA, Bardal AM, Freund KB, Chen KJ, Eandi CM, Blodi B (2006) Idiopathic macular telangiectasia. Arch Ophthalmol 124:450-460.