Targeted Ablation of and in Retinal Progenitor Cells Mimics Leber Congenital Amaurosis

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Development in the central nervous system is highly dependent on the regulation of the switch from progenitor cell proliferation to differentiation, but the molecular and cellular events controlling this process remain poorly understood. Here, we report that ablation of Crb1 and Crb2 genes results in severe impairment of retinal function, abnormal lamination and thickening of the retina mimicking human Leber congenital amaurosis due to loss of CRB1 function. We show that the levels of CRB1 and CRB2 proteins are crucial for mouse retinal development, as they restrain the proliferation of retinal progenitor cells. The lack of these apical proteins results in altered cell cycle progression and increased number of mitotic cells leading to an increased number of late-born cell types such as rod photoreceptors, bipolar and Müller glia cells in postmitotic retinas. Loss of CRB1 and CRB2 in the retina results in dysregulation of target genes for the Notch1 and YAP/Hippo signaling pathways and increased levels of P120-catenin. Loss of CRB1 and CRB2 result in altered progenitor cell cycle distribution with a decrease in number of late progenitors in G1 and an increase in S and G2/M phase. These findings suggest that CRB1 and CRB2 suppress late progenitor pool expansion by regulating multiple proliferative signaling pathways.

Vyšlo v časopise: Targeted Ablation of and in Retinal Progenitor Cells Mimics Leber Congenital Amaurosis. PLoS Genet 9(12): e32767. doi:10.1371/journal.pgen.1003976
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003976

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Zdroje

1. AndreazzoliM (2009) Molecular regulation of vertebrate retina cell fate. Birth Defects Res C Embryo Today 87: 284–295.

2. LiveseyFJ, CepkoCL (2001) Vertebrate neural cell-fate determination: lessons from the retina. Nat Rev Neurosci 2: 109–118.

3. YoungRW (1985) Cell differentiation in the retina of the mouse. Anat Rec 212: 199–205.

4. AgathocleousM, HarrisWA (2009) From progenitors to differentiated cells in the vertebrate retina. Annu Rev Cell Dev Biol 25: 45–69.

5. BurmeisterM, NovakJ, LiangMY, BasuS, PloderL, et al. (1996) Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation. Nat Genet 12: 376–384.

6. Martin-BelmonteF, Perez-MorenoM (2011) Epithelial cell polarity, stem cells and cancer. Nat Rev Cancer 12: 23–38.

7. TepassU, TheresC, KnustE (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.

8. BulgakovaNA, KnustE (1990) The Crumbs complex: from epithelial-cell polarity to retinal degeneration. J Cell Sci 122: 2587–2596.

9. KimS, LehtinenMK, SessaA, ZappaterraMW, ChoSH, et al. (2010) The apical complex couples cell fate and cell survival to cerebral cortical development. Neuron 66: 69–84.

10. HerranzH, StamatakiE, FeiguinF, MilánM (2006) Self-refinement of Notch activity through the transmembrane protein Crumbs: modulation of gamma-secretase activity. EMBO Rep 7: 297–302.

11. MitsuishiY, HasegawaH, MatsuoA, ArakiW, SuzukiT, et al. (2010) Human CRB2 inhibits gamma-secretase cleavage of amyloid precursor protein by binding to the presenilin complex. J Biol Chem 285: 14920–14931.

12. OhataS, AokiR, KinoshitaS, YamaguchiM, Tsuruoka-KinoshitaS, et al. (2011) Dual roles of Notch in regulation of apically restricted mitosis and apicobasal polarity of neuroepithelial cells. Neuron 69: 215–230.

13. Massey-HarrocheD, DelgrossiMH, Lane-GuermonprezL, ArsantoJP, BorgJP, et al. (2007) Evidence for a molecular link between the tuberous sclerosis complex and the Crumbs complex. Hum Mol Genet 16: 529–536.

14. ZhaoB, TumanengK, GuanKL (2011) The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat Cell Biol 13: 877–883.

15. ChenCL, GajewskiKM, HamaratogluF, BossuytW, Sansores-GarciaL, et al. (2010) The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila. Proc Natl Acad Sci U S A 107: 15810–15815.

16. RobinsonBS, HuangJ, HongY, MobergKH (2010) Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein Expanded. Curr Biol 20: 582–590.

17. VarelasX, Samavarchi-TehraniP, NarimatsuM, WeissA, CockburnK, et al. (2010) The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway. Dev Cell 19: 831–844.

18. RichardM, RoepmanR, AartsenWM, van RossumAG, den HollanderAI, et al. (2006) Towards understanding CRUMBS function in retinal dystrophies. Hum Mol Genet 15: 235–243.

19. den HollanderAI, RoepmanR, KoenekoopRK, CremersFP (2008) Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res 27: 391–419.

20. JacobsonSG, CideciyanAV, AlemanTS, PiantaMJ, SumarokaA, et al. (2003) Crumbs homolog 1 (CRB1) mutations result in a thick human retina with abnormal lamination. Hum Mol Genet 12: 1073–1078.

21. den HollanderAI, GhianiM, de KokYJ, WijnholdsJ, BallabioA, et al. (2002) Isolation of Crb1, a mouse homologue of Drosophila crumbs, and analysis of its expression pattern in eye and brain. Mech Dev 110: 203–207.

22. AlvesCH, Sanz SanzA, ParkB, PellissierLP, TanimotoN, 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.

23. van RossumAG, AartsenWM, MeulemanJ, KloosterJ, MalyshevaA, et al. (2006) Pals1/Mpp5 is required for correct localization of Crb1 at the subapical region in polarized Muller glia cells. Hum Mol Genet 15: 2659–2672.

24. van de PavertSA, KantardzhievaA, MalyshevaA, MeulemanJ, VersteegI, 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.

25. van de PavertSA, SanzAS, AartsenWM, VosRM, VersteegI, et al. (2007) Crb1 is a determinant of retinal apical Müller glia cell features. Glia 55: 1486–1497.

26. van de PavertSA, MeulemanJ, MalyshevaA, AartsenWM, VersteegI, et al. (2007) 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.

27. MehalowAK, KameyaS, SmithRS, HawesNL, DenegreJM, et al. (2003) CRB1 is essential for external limiting membrane integrity and photoreceptor morphogenesis in the mammalian retina. Hum Mol Genet 12: 2179–2189.

28. RowanS, CepkoCL (2004) Genetic analysis of the homeodomain transcription factor Chx10 in the retina using a novel multifunctional BAC transgenic mouse reporter. Dev Biol 271: 388–402.

29. SakagamiK, GanL, YangXJ (2009) Distinct effects of Hedgehog signaling on neuronal fate specification and cell cycle progression in the embryonic mouse retina. J Neurosci 29: 6932–6944.

30. DasG, ChoiY, SicinskiP, LevineEM (2009) Cyclin D1 fine-tunes the neurogenic output of embryonic retinal progenitor cells. Neural Dev 4: 15.

31. ParkJI, KimSW, LyonsJP, JiH, NguyenTT, et al. (2005) Kaiso/p120-catenin and TCF/beta-catenin complexes coordinately regulate canonical Wnt gene targets. Dev Cell 8: 843–854.

32. ParkJI, JiH, JunS, GuD, HikasaH, et al. (2006) Frodo links Dishevelled to the p120-catenin/Kaiso pathway: distinct catenin subfamilies promote Wnt signals. Dev Cell 11: 683–695.

33. ZhangH, DeoM, ThompsonRC, UhlerMD, TurnerDL (2012) Negative regulation of Yap during neuronal differentiation. Dev Biol 361: 103–115.

34. ReeseBE (2011) Development of the retina and optic pathway. Vision Res 51: 613–632.

35. ChoSH, KimJY, SimonsDL, SongJY, LeJH, et al. (2012) Genetic ablation of Pals1 in retinal progenitor cells models the retinal pathology of Leber congenital amaurosis. Hum Mol Genet 21: 2663–2676.

36. ParkB, AlvesCH, LundvigDM, TanimotoN, BeckSC, et al. (2011) PALS1 is essential for retinal pigment epithelium structure and neural retina stratification. J Neurosci 31: 17230–17241.

37. ChartierNT, OddouCI, LainéMG, DucarougeB, MarieCA, et al. (2007) Cyclin-dependent kinase 2/cyclin E complex is involved in p120 catenin (p120ctn)-dependent cell growth control: a new role for p120ctn in cancer. Cancer Res 67: 9781–9790.

38. JiangG, WangY, DaiS, LiuY, StoeckerM, et al. (2012) P120-catenin isoforms 1 and 3 regulate proliferation and cell cycle of lung cancer cells via β-catenin and Kaiso respectively. PLoS One 7: e30303.

39. AlemanTS, CideciyanAV, AguirreGK, HuangWC, MullinsCL, et al. (2011) Human CRB1-associated retinal degeneration: comparison with the rd8 Crb1-mutant mouse model. Invest Ophthalmol Vis Sci 52: 6898–6910.

40. TrifunovicD, KaraliM, CamposampieroD, PonzinD, BanfiS, et al. (2008) A high-resolution RNA expression atlas of retinitis pigmentosa genes in human and mouse retinas. Invest Ophthalmol Vis Sci 49: 2330–2336.

41. BibbLC, HoltJK, TarttelinEE, HodgesMD, Gregory-EvansK, et al. (2001) Temporal and spatial expression patterns of the CRX transcription factor and its downstream targets. Critical differences during human and mouse eye development. Hum Mol Genet 10: 1571–1579.

42. DonovanSL, SchweersB, MartinsR, JohnsonD, DyerMA (2006) Compensation by tumor suppressor genes during retinal development in mice and humans. BMC Biol 4: 14.

43. BujakowskaK, AudoI, Mohand-SaïdS, LancelotME, AntonioA, et al. (2012) CRB1 mutations in inherited retinal dystrophies. Hum Mutat 33: 306–315.

44. van den HurkJA, RashbassP, RoepmanR, DavisJ, VoesenekKE, et al. (2005) Characterization of the Crumbs homolog 2 (CRB2) gene and analysis of its role in retinitis pigmentosa and Leber congenital amaurosis. Mol Vis 11: 263–273.

45. TanimotoN, MuehlfriedelRL, FischerMD, FahlE, HumphriesP, et al. (2009) Vision tests in the mouse: functional phenotyping with electroretinography. Front Biosci 14: 2730–2737.

46. SeeligerMW, BeckSC, Pereyra-MuñozN, DangelS, TsaiJY, et al. (2005) In vivo confocal imaging of the retina in animal models using scanning laser ophthalmoscopy. Vision Res 45: 3512–3519.

47. FischerMD, HuberG, BeckSC, TanimotoN, MuehlfriedelR, et al. (2009) Non invasive, in vivo assessment of mouse retinal structure using optical coherence tomography. PLoS One 4: e7507.