Nanda Boon, Jan Wijnholds, and Lucie P. Pellissier | Frontier Neuroscience | Vol 14 | 2020 Aug 14 | doi.org/10.3389/fnins.2020.00860
Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are inherited degenerative retinal dystrophies with vision loss that ultimately lead to blindness. Several genes have been shown to be involved in early onset retinal dystrophies, including CRB1 and RPE65. Gene therapy recently became available for young RP patients with variations in the RPE65 gene. Current research programs test adeno-associated viral gene augmentation or editing therapy vectors on various disease models mimicking the disease in patients. These include several animal and emerging human-derived models, such as human-induced pluripotent stem cell (hiPSC)-derived retinal organoids or hiPSC-derived retinal pigment epithelium (RPE), and human donor retinal explants. Variations in the CRB1 gene are a major cause for early onset autosomal recessive RP with patients suffering from visual impairment before their adolescence and for LCA with newborns experiencing severe visual impairment within the first months of life. These patients cannot benefit yet from an available gene therapy treatment. In this review, we will discuss the recent advances, advantages and disadvantages of different CRB1 human and animal retinal degeneration models. In addition, we will describe novel therapeutic tools that have been developed, which could potentially be used for retinal gene augmentation therapy for RP patients with variations in the CRB1 gene.
CRB Family Members
Crumbs (Crb) is a large transmembrane protein initially discovered at the apical membrane of Drosophila epithelial cells (Tepass et al., 1990). Several years later, it was found that mutations in a human homolog of the Drosophila melanogaster protein crumbs, denoted as CRB1 (Crumbs homolog 1), was involved in retinal dystrophies in humans (Den Hollander et al., 1999). The human CRB1 gene is mapped to chromosome 1q31.3, and contains 12 exons, has 12 identified transcript variants so far, three CRB family members, and over 210 kb genomic DNA (Den Hollander et al., 1999)1. Canonical CRB1 is, like its Drosophila homolog, a large transmembrane protein consisting of multiple epidermal growth factor (EGF) and laminin-globular like domains in its extracellular N-terminus (Figure 1A). The intracellular C-terminal domain contains a FERM and a conserved glutamic acid-arginine-leucine-isoleucine (ERLI) PDZ binding motives. An alternative transcript of CRB1, CRB1-B, was recently described and suggested to have significant extracellular domain overlap with canonical CRB1 while bearing unique 5′ and 3′ domains (Ray et al., 2020). In mammals, CRB1 is a member of the Crumbs family together with CRB2 and CRB3 (Figure 1A). CRB2 displays almost the same protein structure as CRB1, except a depletion of four EGF domains. CRB3A lacks the entire typical extracellular domain but contains the transmembrane domain juxtaposed to the intracellular part with the FERM-binding motif and a ERLI PDZ sequence. A second protein (isoform CRB3B) arises from the same CRB3 gene due to alternate splicing of the last exon, resulting in a different C-terminus with a cysteine-leucine-proline-isoleucine (CLPI) amino acid sequence, and thus lacks the PDZ domain (Fan et al., 2007; Margolis, 2018). Interestingly, the CRB3B isoform is found in mammals, but not in zebrafish or Drosophila (Fan et al., 2007). Further details about CRB isoform details can be found in Quinn et al. (2017).
References
Adachi, M., Hamazaki, Y., Kobayashi, Y., Itoh, M., Tsukita, S., Furuse, M., et al. (2009). Similar and distinct properties of MUPP1 and Patj, two homologous PDZ domain-containing tight-junction proteins. Mol. Cell. Biol. 29, 2372–2389. doi: 10.1128/mcb.01505-08
Aguilar-Aragon, M., Fletcher, G., and Thompson, B. J. (2020). The cytoskeletal motor proteins Dynein and MyoV direct apical transport of crumbs. Dev. Biol. 459, 126–137. doi: 10.1016/j.ydbio.2019.12.009
Ahmed, S. M., and Macara, I. G. (2017). The Par3 polarity protein is an exocyst receptor essential for mammary cell survival. Nat. Commun. 8:14867. doi: 10.1038/ncomms14867
Akelley, R. A., Conley, S. M., Makkia, R., Watson, J. N., Han, Z., Cooper, M. J., et al. (2018). DNA nanoparticles are safe and nontoxic in non-human primate eyes. Int. J. Nanomedicine 13, 1361–1379. doi: 10.2147/IJN.S157000
Alves, C. H., Boon, N., Mulder, A. A., Koster, A. J., Jost, C. R., and Wijnholds, J. (2019). CRB2 loss in rod photoreceptors is associated with progressive loss of retinal contrast sensitivity. Int. J. Mol. Sci. 20:4069. doi: 10.3390/ijms20174069
Alves, C. H., Pellissier, L. P., Vos, R. M., Garrido, M. G., Sothilingam, V., Seide, C., et al. (2014). Targeted ablation of Crb2 in photoreceptor cells induces retinitis pigmentosa. Hum. Mol. Genet. 23, 3384–3401. doi: 10.1093/hmg/ddu048
Alves, C. H., Sanz sanz, A., Park, B., Pellissier, L. P., Tanimoto, N., Beck, S. C., et al. (2013). Loss of CRB2 in the mouse retina mimics human retinitis pigmentosa due to mutations in the CRB1 gene. Hum. Mol. Genet. 22, 35–50. doi: 10.1093/hmg/dds398
Assémat, E., Crost, E., Ponserre, M., Wijnholds, J., Le Bivic, A., and Massey-Harroche, D. (2013). The multi-PDZ domain protein-1 (MUPP-1) expression regulates cellular levels of the PALS-1/PATJ polarity complex. Exp. Cell Res. 319, 2514–2525. doi: 10.1016/j.yexcr.2013.07.011
Bazellières, E., Aksenova, V., Barthélémy-Requin, M., Massey-Harroche, D., and Le Bivic, A. (2018). Role of the Crumbs proteins in ciliogenesis, cell migration and actin organization. Semin. Cell Dev. Biol. 81, 13–20. doi: 10.1016/j.semcdb.2017.10.018
Buchholz, D. E., Pennington, B. O., Croze, R. H., Hinman, C. R., Coffey, P. J., and Clegg, D. O. (2013). Rapid and efficient directed differentiation of human pluripotent stem cells into retinal pigmented epithelium. Stem Cells Transl. Med. 2, 384–393. doi: 10.5966/sctm.2012-0163
Buck, T. M., and Wijnholds, J. (2020). Recombinant adeno-associated viral vectors (rAAV)-vector elements in ocular gene therapy clinical trials and transgene expression and bioactivity assays. Int. J. Mol. Sci. 21:4197. doi: 10.3390/ijms21124197
Bujakowska, K., Audo, I., Mohand-Säid, S., Lancelot, M. E., Antonio, A., Germain, A., et al. (2012). CRB1 mutations in inherited retinal dystrophies. Hum. Mutat. 33, 306–315. doi: 10.1002/humu.21653
Bulgakova, N. A., and Knust, E. (2009). The crumbs complex: from epithelial-cell polarity to retinal degeneration. J. Cell Sci. 122, 2587–2596. doi: 10.1242/jcs.023648
Cai, X., Nash, Z., Conley, S. M., Fliesler, S. J., Cooper, M. J., and Naash, M. I. (2009). A partial structural and functional rescue of a retinitis pigmentosa model with compacted DNA nanoparticles. PLoS One 4:e0005290. doi: 10.1371/journal.pone.0005290
Capowski, E. E., Samimi, K., Mayerl, S. J., Phillips, M. J., Pinilla, I., Howden, S. E., et al. (2019). Reproducibility and staging of 3D human retinal organoids across multiple pluripotent stem cell lines. Development 146:dev171686. doi: 10.1242/dev.171686
Carvalho, L. S., Turunen, H. T., Wassmer, S. J., Luna-Velez, M. V., Xiao, R., Bennett, J., et al. (2017). Evaluating efficiencies of dual AAV approaches for retinal targeting. Front. Neurosci. 11:503. doi: 10.3389/fnins.2017.00503
Chartier, F. J. M., Hardy, ÉJ. L., and Laprise, P. (2011). Crumbs controls epithelial integrity by inhibiting Rac1 and PI3K. J. Cell Sci. 124, 3393–3398. doi: 10.1242/jcs.092601
Chen, X., Jiang, C., Yang, D., Sun, R., Wang, M., Sun, H., et al. (2019). CRB2 mutation causes autosomal recessive retinitis pigmentosa. Exp. Eye Res. 180, 164–173. doi: 10.1016/j.exer.2018.12.018
Chichagova, V., Hilgen, G., Ghareeb, A., Georgiou, M., Carter, M., Sernagor, E., et al. (2020). Human iPSC differentiation to retinal organoids in response to IGF1 and BMP4 activation is line- and method-dependent. Stem Cells 38, 195–201. doi: 10.1002/stem.3116
Cora, V., Haderspeck, J., Antkowiak, L., Mattheus, U., Neckel, P. H., Mack, A. F., et al. (2019). A cleared view on retinal organoids. Cells 8:391. doi: 10.3390/cells8050391
Corton, M., Tatu, S. D., Avila-Fernandez, A., Vallespín, E., Tapias, I., Cantalapiedra, D., et al. (2013). High frequency of CRB1 mutations as cause of early-onset retinal dystrophies in the Spanish population. Orphanet J. Rare Dis. 8:20. doi: 10.1186/1750-1172-8-20
Den Hollander, A. I., Davis, J., Van Der Velde-Visser, S. D., Zonneveld, M. N., Pierrottet, C. O., Koenekoop, R. K., et al. (2004). CRB1 mutation spectrum in inherited retinal dystrophies. Hum. Mutat. 24, 355–369. doi: 10.1002/humu.20093
Den Hollander, A. I., Ten Brink, J. B., De Kok, Y. J. M., Van Soest, S., Van Den Born, L. I., Van Driel, M. A., et al. (1999). Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12). Nat. Genet. 23, 217–221. doi: 10.1038/13848
Ding, X., and Gradinaru, V. (2020). “Structure-guided rational design of adeno-associated viral capsids with expanded sizes,” in Proceedings of the 23rd Annual Meeting of the American Society for Gene and Cell Therapy, Milwaukee, WI.
Ding, X. Q., Quiambao, A. B., Fitzgerald, J. B., Cooper, M. J., Conley, S. M., and Naash, M. I. (2009). Ocular delivery of compacted DNA-nanoparticles does not elicit toxicity in the mouse retina. PLoS One 4:e0007410. doi: 10.1371/journal.pone.0007410
Dudok, J. J., Murtaza, M., Alves, H. C., Rashbass, P., and Wijnholds, J. (2016). Crumbs 2 prevents cortical abnormalities in mouse dorsal telencephalon. Neurosci. Res. 108, 12–23. doi: 10.1016/j.neures.2016.01.001
Dudok, J. J., Sanz, A. S., Lundvig, D. M. S., Sothilingam, V., Garrido, M. G., Klooster, J., et al. (2013). MPP3 regulates levels of PALS1 and adhesion between photoreceptors and Müller cells. Glia 61, 1629–1644. doi: 10.1002/glia.22545
Ebarasi, L., Ashraf, S., Bierzynska, A., Gee, H. Y., McCarthy, H. J., Lovric, S., et al. (2015). Defects of CRB2 cause steroid-resistant nephrotic syndrome. Am. J. Hum. Genet. 96, 153–161. doi: 10.1016/j.ajhg.2014.11.014
Fan, S., Fogg, V., Wang, Q., Chen, X. W., Liu, C. J., and Margolis, B. (2007). A novel Crumbs3 isoform regulates cell division and ciliogenesis via importin β interactions. J. Cell Biol. 178, 387–398. doi: 10.1083/jcb.200609096
Fink, T. L., Klepcyk, P. J., Oette, S. M., Gedeon, C. R., Hyatt, S. L., Kowalczyk, T. H., et al. (2006). Plasmid size up to 20 kbp does not limit effective in vivo lung gene transfer using compacted DNA nanoparticles. Gene Ther. 13, 1048–1051. doi: 10.1038/sj.gt.3302761
Gao, Y., Lui, W. Y., Lee, W. M., and Cheng, C. Y. (2016). Polarity protein Crumbs homolog-3 (CRB3) regulates ectoplasmic specialization dynamics through its action on F-actin organization in Sertoli cells. Sci. Rep. 6, 1–20. doi: 10.1038/srep28589
Garita-Hernandez, M., Routet, F., Guibbal, L., Khabou, H., Toualbi, L., Riancho, L., et al. (2020). AAV-mediated gene delivery to 3D retinal organoids derived from human induced pluripotent stem cells. Int. J. Mol. Sci. 21, 1–16. doi: 10.3390/ijms21030994
Gosens, I., Sessa, A., den Hollander, A. I., Letteboer, S. J. F., Belloni, V., Arends, M. L., et al. (2007). FERM protein EPB41L5 is a novel member of the mammalian CRB-MPP5 polarity complex. Exp. Cell Res. 313, 3959–3970. doi: 10.1016/j.yexcr.2007.08.025
Hallam, D., Hilgen, G., Dorgau, B., Zhu, L., Yu, M., Bojic, S., et al. (2018). Human-induced pluripotent stem cells generate light responsive retinal organoids with variable and nutrient-dependent efficiency. Stem Cells 36, 1535–1551. doi: 10.1002/stem.2883
Hamon, A., García-García, D., Ail, D., Bitard, J., Chesneau, A., Dalkara, D., et al. (2019). Linking YAP to müller glia quiescence exit in the degenerative retina. Cell Rep. 27, 1712.e6–1725.e6. doi: 10.1016/j.celrep.2019.04.045
Hamon, A., Masson, C., Bitard, J., Gieser, L., Roger, J. E., and Perron, M. (2017). Retinal degeneration triggers the activation of YAP/TEAD in reactive Müller cells. Retin. Cell Biol. 58, 1941–1953. doi: 10.1167/iovs.16-21366
Han, Z., Conley, S. M., Makkia, R., Guo, J., Cooper, M. J., and Naash, M. I. (2012). Comparative analysis of DNA nanoparticles and AAVs for ocular gene delivery. PLoS One 7:e0052189. doi: 10.1371/journal.pone.0052189
Henderson, R. H., Mackay, D. S., Li, Z., Moradi, P., Sergouniotis, P., Russell-Eggitt, I., et al. (2011). Phenotypic variability in patients with retinal dystrophies due to mutations in CRB1. Br. J. Ophthalmol. 95, 811–817. doi: 10.1136/bjo.2010.186882
Hu, Y., Wang, X., Hu, B., Mao, Y., Chen, Y., Yan, L., et al. (2019). Dissecting the transcriptome landscape of the human fetal neural retina and retinal pigment epithelium by single-cell RNA-seq analysis. PLoS Biol. 17:e3000365. doi: 10.1371/journal.pbio.3000365
Hurd, T. W., Gao, L., Roh, M. H., Macara, I. G., and Margolis, B. (2003). Direct interaction of two polarity complexes implicated in epthelial tight junction assembly. Nat. Cell Biol. 5, 137–142. doi: 10.1038/ncb923
Joberty, G., Petersen, C., Gao, L., and Macara, I. G. (2000). The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42. Nat. Cell Biol. 2, 531–539. doi: 10.1038/35019573
Kantardzhieva, A., Alexeeva, S., Versteeg, I., and Wijnholds, J. (2006). MPP3 is recruited to the MPP5 protein scaffold at the retinal outer limiting membrane. FEBS J. 273, 1152–1165. doi: 10.1111/j.1742-4658.2006.05140.x
Kantardzhieva, A., Gosens, I., Alexeeva, S., Punte, I. M., Versteeg, I., Krieger, E., et al. (2005). MPP5 recruits MPP4 to the CRB1 complex in photoreceptors. Investig. Ophthalmol. Vis. Sci. 46, 2192–2201. doi: 10.1167/iovs.04-1417
Kim, S., Lowe, A., Dharmat, R., Lee, S., Owen, L. A., Wang, J., et al. (2019). Generation, transcriptome profiling, and functional validation of cone-rich human retinal organoids. Proc. Natl. Acad. Sci. U.S.A. 166, 10824–10833. doi: 10.1073/pnas.1901572116
Kraut, R. S., and Knust, E. (2019). Changes in endolysosomal organization define a pre-degenerative state in the crumbs mutant Drosophila retina. PLoS One 14:e0220220. doi: 10.1371/journal.pone.0220220
Lane, A., Jovanovic, K., Shortall, C., Ottaviani, D., Panes, A. B., Schwarz, N., et al. (2020). Modeling and rescue of RP2 retinitis pigmentosa using iPSC-derived retinal organoids. Stem Cell Rep. 15, 1–13. doi: 10.1016/j.stemcr.2020.05.007
Laprise, P., Beronja, S., Silva-gagliardi, N. F., Pellikka, M., Jensen, M., Mcglade, C. J., et al. (2006). The FERM protein yurt is a negative regulatory component of the crumbs complex that controls epithelial polarity and apical membrane size. Dev. Cell 11, 363–374. doi: 10.1016/j.devcel.2006.06.001
Laprise, P., Lau, K. M., Harris, K. P., Silva-Gagliardi, N. F., Paul, S. M., Beronja, S., et al. (2009). Yurt, Coracle, Neurexin IV and the Na+, K+-ATPase form a novel group of epithelial polarity proteins. Nature 459, 1141–1145. doi: 10.1038/nature08067
Lee, J. D., Silva-Gagliardi, N. F., Tepass, U., McGlade, C. J., and Anderson, K. V. (2007). The FERM protein Epb4.1I5 is required for organization of the neural plate and for the epithelial-mesenchymal transition at the primitive streak of the mouse embryo. Development 134, 2007–2016. doi: 10.1242/dev.000885
Lemmers, C., Michel, D., Lane-Guermonprez, L., Delgrossi, M.-H., Médina, E., Arsanto, J. P., et al. (2004). CRB3 binds directly to Par6 and regulates the morphogenesis of the tight junctions in mammalian epithelial cells. Mol. Biol. Cell 15, 1324–1333. doi: 10.1091/mbc.E03
Li, B. X., Satoh, A. K., and Ready, D. F. (2007). Myosin V, Rab11, and dRip11 direct apical secretion and cellular morphogenesis in developing Drosophila photoreceptors. J. Cell Biol. 177, 659–669. doi: 10.1083/jcb.200610157
Lin, D., Edwards, A. S., Fawcett, J. P., Mbamalu, G., Scott, J. D., and Pawson, T. (2000). A mammalian PAR-3-PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity. Nat. Cell Biol. 2, 540–547. doi: 10.1038/35019582
Luo, Z., Zhong, X., Li, K., Xie, B., Liu, Y., Ye, M., et al. (2018). An optimized system for effective derivation of three-dimensional retinal tissue via wnt signaling regulation. Stem Cells 36, 1709–1722. doi: 10.1002/stem.2890
Maddalena, A., Tornabene, P., Tiberi, P., Minopoli, R., Manfredi, A., Mutarelli, M., et al. (2018). Triple vectors expand AAV transfer capacity in the retina. Mol. Ther. 26, 524–541. doi: 10.1016/j.ymthe.2017.11.019
Maguire, A. M., Russell, S., Wellman, J. A., Chung, D. C., Yu, Z. F., Tillman, A., et al. (2019). Efficacy, safety, and durability of voretigene Neparvovec-rzyl in RPE65 mutation–associated inherited retinal dystrophy: results of phase 1 and 3 trials. Ophthalmology 126, 1273–1285. doi: 10.1016/j.ophtha.2019.06.017
Mao, X., Li, P., Wang, Y., Liang, Z., Liu, J., Li, J., et al. (2017). CRB3 regulates contact inhibition by activating the Hippo pathway in mammary epithelial cells. Cell Death Dis. 8:e2546. doi: 10.1038/cddis.2016.478
Margolis, B. (2018). The Crumbs3 polarity protein. Cold Spring Harb. Perspect. Biol. 10, 1–9. doi: 10.1101/cshperspect.a027961
Maruotti, J., Sripathi, S. R., Bharti, K., Fuller, J., Wahlin, K. J., Ranganathan, V., et al. (2015). Small-molecule-directed, efficient generation of retinal pigment epithelium from human pluripotent stem cells. Proc. Natl. Acad. Sci. U.S.A. 112, 10950–10955. doi: 10.1073/pnas.1422818112
Mathijssen, I. B., Florijn, R. J., Van Den Born, L. I., Zekveld-Vroon, R. C., Ten Brink, J. B., Plomp, A. S., et al. (2017). Long-term follow-up of patients with retinitis pigmentosa type 12 caused by CRB1 mutations: a severe phenotype with considerable interindividual variability. Retina 37, 161–172. doi: 10.1097/IAE.0000000000001127
Mehalow, A. K., Kameya, S., Smith, R. S., Hawes, N. L., Denegre, J. M., Young, J. A., et al. (2003). CRB1 is essential for external limiting membrane integrity and photoreceptor morphogenesis in the mammalian retina. Hum. Mol. Genet. 12, 2179–2189. doi: 10.1093/hmg/ddg232
Mellough, C. B., Collin, J., Queen, R., Hilgen, G., Dorgau, B., Zerti, D., et al. (2019). Systematic comparison of retinal organoid differentiation from human pluripotent stem cells reveals stage specific, cell line, and methodological differences. Stem Cells Transl. Med. 8, 694–706. doi: 10.1002/sctm.18-0267
Meyer, J. S., Howden, S. E., Wallace, K. A., Verhoeven, A. D., Wright, L. S., Capowski, E. E., et al. (2011). Optic vesicle-like structures derived from human pluripotent stem cells facilitate a customized approach to retinal disease treatment. Stem Cells 29, 1206–1218. doi: 10.1002/stem.674
Michel, D., Arsanto, J. P., Massey-Harroche, D., Béclin, C., Wijnholds, J., and Le Bivic, A. (2005). PATJ connects and stabilizes apical and lateral components of tight junctions in human intestinal cells. J. Cell Sci. 118, 4049–4057. doi: 10.1242/jcs.02528
Nakano, T., Ando, S., Takata, N., Kawada, M., Muguruma, K., Sekiguchi, K., et al. (2012). Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 10, 771–785. doi: 10.1016/j.stem.2012.05.009
Ovando-Roche, P., West, E. L., Branch, M. J., Sampson, R. D., Fernando, M., Munro, P., et al. (2018). Use of bioreactors for culturing human retinal organoids improves photoreceptor yields. Stem Cell Res. Ther. 9, 1–14. doi: 10.1186/s13287-018-0907-0
Park, B., Alves, C. H., Lundvig, D. M., Tanimoto, N., Beck, S. C., Huber, G., et al. (2011). PALS1 is essential for retinal pigment epithelium structure and neural retina stratification. J. Neurosci. 31, 17230–17241. doi: 10.1523/JNEUROSCI.4430-11.2011
Pellikka, M., Tanentzapf, G., Pinto, M., Smith, C., McGlade, C. J., Ready, D. F., et al. (2002). Crumbs, the Drosophila homologue of human CRB1/RP12, is essential for photoreceptor morphogenesis. Nature 416, 143–149. doi: 10.1038/nature721
Pellissier, L. P., Alves, C. H., Quinn, P. M., Vos, R. M., Tanimoto, N., Lundvig, D. M. S., et al. (2013). Targeted ablation of Crb1 and Crb2 in retinal progenitor cells mimics leber congenital amaurosis. PLoS Genet. 9:e1003976. doi: 10.1371/journal.pgen.1003976
Pellissier, L. P., Hoek, R. M., Vos, R. M., Aartsen, W. M., Klimczak, R. R., Hoyng, S. A., et al. (2014a). Specific tools for targeting and expression in Müller glial cells. Mol. Ther. Methods Clin. Dev. 1:14009. doi: 10.1038/mtm.2014.9
Pellissier, L. P., Lundvig, D. M. S., Tanimoto, N., Klooster, J., Vos, R. M., Richard, F., et al. (2014b). CRB2 acts as a modifying factor of CRB1-related retinal dystrophies in mice. Hum. Mol. Genet. 23, 3759–3771. doi: 10.1093/hmg/ddu089
Pellissier, L. P., Quinn, P. M., Henrique Alves, C., Vos, R. M., Klooster, J., Flannery, J. G., et al. (2015). Gene therapy into photoreceptors and Muller glial cells restores retinal structure and function in CRB1 retinitis pigmentosa mouse models. Hum. Mol. Genet. 24, 3104–3118. doi: 10.1093/hmg/ddv062
Pichaud, F. (2018). PAR-Complex and crumbs function during photoreceptor morphogenesis and retinal degeneration. Front. Cell. Neurosci. 12:90. doi: 10.3389/fncel.2018.00090
Pocha, S. M., Shevchenko, A., and Knust, E. (2011). Crumbs regulates rhodopsin transport by interacting with and stabilizing myosin V. J. Cell Biol. 195, 827–838. doi: 10.1083/jcb.201105144
Polgar, N., and Fogelgren, B. (2018). Regulation of cell polarity by exocyst-mediated traffickin. Cold Spring Harb. Perspect. Biol. 10:a031401. doi: 10.1101/cshperspect.a031401
Quinn, P. M., Alves, C. H., Klooster, J., and Wijnholds, J. (2018). CRB2 in immature photoreceptors determines the superior-inferior symmetry of the developing retina to maintain retinal structure and function. Hum. Mol. Genet. 27, 3137–3153. doi: 10.1093/hmg/ddy194
Quinn, P. M., Mulder, A. A., Henrique Alves, C., Desrosiers, M., de Vries, S. I., Klooster, J., et al. (2019b). Loss of CRB2 in Müller glial cells modifies a CRB1-associated retinitis pigmentosa phenotype into a Leber congenital amaurosis phenotype. Hum. Mol. Genet. 28, 105–123. doi: 10.1093/hmg/ddy337
Quinn, P. M., Pellissier, L. P., and Wijnholds, J. (2017). The CRB1 complex: following the trail of crumbs to a feasible gene therapy strategy. Front. Neurosci. 11:175. doi: 10.3389/fnins.2017.00175
Ray, T. A., Cochran, K., Kozlowski, C., Wang, J., Alexander, G., Cady, M. A., et al. (2020). Comprehensive identification of mRNA isoforms reveals the diversity of neural cell-surface molecules with roles in retinal development and disease. Nat. Commun. 11:3328. doi: 10.1038/s41467-020-17009-7
Roh, M. H., Makarova, O., Liu, C. J., Shin, K., Lee, S., Laurinec, S., et al. (2002). The Maguk protein, Pals1, functions as an adapter, linking mammalian homologues of crumbs and discs lost. J. Cell Biol. 157, 161–172. doi: 10.1083/jcb.200109010
Rueda, E. M., Hall, B. M., Hill, M. C., Swinton, P. G., Tong, X., Martin, J. F., et al. (2019). The hippo pathway blocks mammalian retinal müller glial cell reprogramming. Cell Rep. 27, 1637.e6–1649.e6. doi: 10.1016/j.celrep.2019.04.047
Shutova, M. V., Surdina, A. V., Ischenko, D. S., Naumov, V. A., Bogomazova, A. N., Vassina, E. M., et al. (2016). An integrative analysis of reprogramming in human isogenic system identified a clone selection criterion. Cell Cycle 15, 986–997. doi: 10.1080/15384101.2016.1152425
Slavotinek, A., Kaylor, J., Pierce, H., Cahr, M., Deward, S. J., Schneidman-Duhovny, D., et al. (2015). CRB2 mutations produce a phenotype resembling congenital nephrosis, Finnish type, with cerebral ventriculomegaly and raised alpha-fetoprotein. Am. J. Hum. Genet. 96, 162–169. doi: 10.1016/j.ajhg.2014.11.013
Smith, E. N., D’Antonio-Chronowska, A., Greenwald, W. W., Borja, V., Aguiar, L. R., Pogue, R., et al. (2019). Human iPSC-derived retinal pigment epithelium: a model system for prioritizing and functionally characterizing causal variants at AMD risk loci. Stem Cell Rep. 12, 1342–1353. doi: 10.1016/j.stemcr.2019.04.012
Suzuki, A., Yamanaka, T., Hirose, T., Manabe, N., Mizuno, K., Shimizu, M., et al. (2001). Atypical protein kinase C is involved in the evolutionarily conserved PAR protein complex and plays a critical role in establishing epithelia-specific junctional structures. J. Cell Biol. 152, 1183–1196. doi: 10.1083/jcb.152.6.1183
Szymaniak, A. D., Mahoney, J. E., Cardoso, W. V., and Varelas, X. (2015). Crumbs3-mediated polarity directs airway epithelial cell fate through the hippo pathway effector yap. Dev. Cell 34, 283–296. doi: 10.1016/j.devcel.2015.06.020
Tait, C., Chinnaiya, K., Manning, E., Murtaza, M., Ashton, J.-P., Furley, N., et al. (2020). Crumbs2 mediates ventricular layer remodelling to form the spinal cord central canal. PLoS Biol. 18:e3000470. doi: 10.1371/journal.pbio.3000470
Talib, M., van Schooneveld, M. J., van Genderen, M. M., Wijnholds, J., Florijn, R. J., ten Brink, J. B., et al. (2017). Genotypic and phenotypic characteristics of CRB1-associated retinal dystrophies: a long-term follow-up study. Ophthalmology 124, 884–895. doi: 10.1016/j.ophtha.2017.01.047
Tepass, U., Theres, C., and Knust, E. (1990). crumbs encodes an EGF-like protein expressed on apical membranes of Drosophila epithelial cells and required for organization of epithelia. Cell 61, 787–799. doi: 10.1016/0092-8674(90)90189-L
Tilston-Lünel, A. M., Haley, K. E., Schlecht, N. F., Wang, Y., Chatterton, A. L. D., Moleirinho, S., et al. (2016). Crumbs 3b promotes tight junctions in an ezrin-dependent manner in mammalian cells. J. Mol. Cell Biol. 8, 439–455. doi: 10.1093/jmcb/mjw020
Trapani, I., Colella, P., Sommella, A., Iodice, C., Cesi, G., de Simone, S., et al. (2014). Effective delivery of large genes to the retina by dual AAV vectors. EMBO Mol. Med. 6, 194–211. doi: 10.1002/emmm.201302948
Vallespin, E., Cantalapiedra, D., Riveiro-Alvarez, R., Wilke, R., Aguirre-Lamban, J., Avila-Fernandez, A., et al. (2007). Mutation screening of 299 Spanish families with retinal dystrophies by leber congenital amaurosis genotyping microarray. Investig. Ophthalmol. Vis. Sci. 48, 5653–5661. doi: 10.1167/iovs.07-0007
van de Pavert, S. A., Kantardzhieva, A., Malysheva, A., Meuleman, J., Versteeg, I., Levelt, C., et al. (2004). Crumbs homologue 1 is required for maintenance of photoreceptor cell polarization and adhesion during light exposure. J. Cell Sci. 117, 4169–4177. doi: 10.1242/jcs.01301
van de Pavert, S. A., Meuleman, J., Malysheva, A., Aartsen, W. M., Versteeg, I., Tonagel, F., et al. (2007a). A single amino acid substitution (Cys249Trp) in Crb1 causes retinal degeneration and deregulates expression of pituitary tumor transforming gene Pttg1. J. Neurosci. 27, 564–573. doi: 10.1523/JNEUROSCI.3496-06.2007
van de Pavert, S. A., Sanz sanz, A., Aartsen, W. M., Vos, R. M., Versteeg, I., Beck, S. C., et al. (2007b). Crb1 is a determinant of retinal apical muller glia cell features. Glia 55, 1486–1497. doi: 10.1002/glia
van Rossum, A. G. S. H., Aartsen, W. M., Meuleman, J., Klooster, J., Malysheva, A., Versteeg, I., et al. (2006). Pals1/Mpp5 is required for correct localization of Crb1 at the subapical region in polarized Müller glia cells. Hum. Mol. Genet. 15, 2659–2672. doi: 10.1093/hmg/ddl194
Verbakel, S. K., van Huet, R. A. C., Boon, C. J. F., den Hollander, A. I., Collin, R. W. J., Klaver, C. C. W., et al. (2018). Non-syndromic retinitis pigmentosa. Prog. Retin. Eye Res. 66, 157–186. doi: 10.1016/j.preteyeres.2018.03.005
Wang, D., Tai, P. W. L., and Gao, G. (2019). Adeno-associated virus vector as a platform for gene therapy delivery. Nat. Rev. Drug Discov. 18, 358–378. doi: 10.1038/s41573-019-0012-9
Wang, Y., Rajala, A., and Rajala, R. V. S. (2018). Nanoparticles as delivery vehicles for the treatment of retinal degenerative diseases. Adv. Exp. Med. Biol. 1074, 117–123. doi: 10.1007/978-3-319-75402-4_15
Whiteman, E. L., Fan, S., Harder, J. L., Walton, K. D., Liu, C.-J., Soofi, A., et al. (2014). Crumbs3 is essential for proper epithelial development and viability. Mol. Cell. Biol. 34, 43–56. doi: 10.1128/mcb.00999-13
Whitney, D. S., Peterson, F. C., Kittel, A. W., Egner, J. M., Prehoda, K. E., and Volkman, B. F. (2016). Crumbs binding to the Par-6 CRIB-PDZ module is regulated by Cdc42. Biochemistry 55, 1455–1461.
Yamanaka, T., Horikoshi, Y., Suzuki, A., Sugiyama, Y., Kitamura, K., Maniwa, R., et al. (2001). PAR-6 regulates aPKC activity in a novel way and mediates cell-cell contact-induces formation of the epithelial junctional complex. Genes Cells 6, 721–731. doi: 10.1046/j.1365-2443.2001.00453.x
Yu, F., and Guan, K. (2013). The Hippo pathway: regulators and regulations. Genes Dev. 27, 335–371. doi: 10.1101/gad.210773.112.a
Yu, F., Zhao, B., and Guan, K. (2015). Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell 163, 811–828. doi: 10.1016/j.cell.2015.10.044
Zahabi, A., Shahbazi, E., Ahmadieh, H., Hassani, S. N., Totonchi, M., Taei, A., et al. (2012). A new efficient protocol for directed differentiation of retinal pigmented epithelial cells from normal and retinal disease induced pluripotent stem cells. Stem Cells Dev. 21, 2262–2272. doi: 10.1089/scd.2011.0599
Zhang, X., Zhang, D., Chen, S. C., Lamey, T., Thompson, J. A., McLaren, T., et al. (2018). Establishment of an induced pluripotent stem cell line from a retinitis pigmentosa patient with compound heterozygous CRB1 mutation. Stem Cell Res. 31, 147–151. doi: 10.1016/j.scr.2018.08.001
Zhao, M., Andrieu-Soler, C., Kowalczuk, L., Paz Cortés, M., Berdugo, M., Dernigoghossian, M., et al. (2015). A new CRB1 rat mutation links müller glial cells to retinal telangiectasia. J. Neurosci. 35, 6093–6106. doi: 10.1523/jneurosci.3412-14.2015
Zhong, X., Gutierrez, C., Xue, T., Hampton, C., Vergara, M. N., Cao, L. H., et al. (2014). Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat. Commun. 5:4047. doi: 10.1038/ncomms5047
Comments