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Overexpression of SIK2 Inhibits FGF2-dependent Müller Glial Reprogramming

Year 2025, Volume: 15 Issue: 1, 23 - 30, 16.04.2025
https://doi.org/10.26650/experimed.1536826

Abstract

Objective: Upon injury, Müller cells re-enter the cell cycle, acquire progenitor properties, and produce new retinal neurons in zebrafish. Proliferation is an essential step in retinal regeneration. The strict regulation of Müller cell proliferation limits mammalian retinal regeneration. Growth factors such as fibroblast growth factor 2 (FGF2) can promote the proliferation of Müller glia in mammals; however, the regeneration capacity is restricted. In this study, we investigated the possible contribution of salt-inducible kinase 2 (SIK2) to Müller reprogramming through FGF2 signaling.

Materials and Methods: MIO-M1 cells were used as the model system. Modulations in cell proliferation, extracellular signal-regulated kinase (ERK)1/2 activity, and SIK2 expression during 7 days of FGF2 treatment were documented. Overexpression studies were conducted to provide clues for the potential contribution of SIK2 to MIO-M1 reprogramming.

Results: Our findings demonstrate that the expansion of Müller cells that de-differentiate into progenitors requires ERK activation. A significant reduction in the SIK2 protein level is necessary for Müller cells to proliferate. SIK2 overexpression inhibited ERK activity, cell proliferation, and reprogramming.

Conclusion: We propose that SIK2 is involved in Müller reprogramming by suppressing ERK activation.

Ethical Statement

Ethical approval: Not applicable.

Supporting Institution

This study was supported by funding from the Bogazici University Research Projects (8921); TÜBİTAK (113Z108); and ÖYP (2012K120490).

Project Number

Bogazici University Research Projects (8921), TÜBİTAK (113Z108), ÖYP (2012K120490)

Thanks

The authors would like to thank Dr. Gamze Küser-Abali (Monash University, Australia) and Dr. Yeliz Yilmaz (İzmir Biomedicine and Genome Center, Turkey) for their feedback and critical reading of the manuscript during its preparation.

References

  • 1. Vecino E, Rodriguez FD, Ruzafa N, Pereiro X, Sharma SC. Glia-neuron interactions in the mammalian retina. Prog Retin Eye Res 2016; 51: 1-40. google scholar
  • 2. Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov S, et al. Müller cells in the healthy and diseased retina. Prog Retin Eye Res 2006; 25(4): 397-424. google scholar
  • 3. Frasson M, Picaud S, Leveillard T, Simonutti M, Mohand-Said S, Dreyfus H, et al. Glial cell line-derived neurotrophic factor induces histologic and functional protection of rod photoreceptors in the rd/rd mouse. İnvest Ophthalmol Vis Sci 1999; 40(11): 2724-34. google scholar
  • 4. Honjo M, Tanihara H, Kido N, İnatani M, Okazaki K, Honda Y. Expression of ciliary neurotrophic factor activated by retinal Müller cells in eyes with NMDA-and kainic acid-induced neuronal death. İnvest Ophthalmol Vis Sci 2000; 41(2): 552-60. google scholar
  • 5. Takeda M, Takamiya A, Yoshida A, Kiyama H. Extracellular signal-regulated kinase activation predominantly in Müller cells of retina with endotoxin-induced uveitis. Invest Ophthalmol Vis Scİ 2002; 43(4): 907-11. google scholar
  • 6. Tezel G, Chauhan BC, LeBlanc RP, Wax MB. Immunohistochemical assessment of the glial mitogen-activated protein kinase activation in glaucoma. Invest Ophthalmol Vis Sci 2003; 44(7): 3025-33. google scholar
  • 7. Dyer MA, Cepko CL. Control of Müller glial cell proliferation and activation following retinal injury. Nat Neurosci 2000; 3(9): 873-80. google scholar
  • 8. Bernardos RL, Barthel LK, Meyers JR, Raymond PA. Late-stage neuronal progenitors in the retina are radial Müller glia that function as retinal stem cells. J Neurosci 2007; 27(26): 7028-40. google scholar
  • 9. Fischer AJ, Reh TA. Müller glia are a potential source of neural regeneration in the postnatal chicken retina. Nat Neurosci 2001; 4(3): 247-52. google scholar
  • 10. Karl MO, Reh TA. Regenerative medicine for retinal diseases: activating endogenous repair mechanisms. Trends Mol Med 2010; 16(4): 193-202. google scholar
  • 11. Hamon A, Roger JE, Yang XJ, Perron M. Müller glial cell-dependent regeneration of the neural retina: An overview across vertebrate model systems. Dev Dyn 2016; 245(7): 727-38. google scholar
  • 12. Limb GA, Salt TE, Munro PMG, Moss SE, Khaw PT. In vitro characterization of a spontaneously immortalized human Müller cell line (MIO-M1). Invest Ophthalmol Vis Sci 2002; 43(3): 864-9. google scholar
  • 13. Lawrence JM, Singhal S, Bhatia B, Keegan DJ, Reh TA, Luthert PJ, et al. MIO-M1 cells and similar muller glial cell lines derived from adult human retina exhibit neural stem cell characteristics. Stem Cells 2007; 25(8): 2033-43. google scholar
  • 14. Bhatia B, Jayaram H, Singhal S, Jones MF, Limb GA. Differences between the neurogenic and proliferative abilities of Müller glia with stem cell characteristics and the ciliary epithelium from the adult human eye. Exp Eye Res 2011; 93(6): 852-61. google scholar
  • 15. Fischer AJ, McGuire CR, Dierks BD, Reh TA. Insulin and fibroblast growth factor 2 activate a neurogenic program in Müller glia of the chicken retina. J Neurosci 2002; 22(21): 9387-98. google scholar
  • 16. Fischer AJ, Scott MA, Tuten W. Mitogen-activated protein kinase-signaling stimulates Müller glia to proliferate in acutely damaged chicken retina. Glia 2009; 57(2): 166-81. google scholar
  • 17. Horike N, Takemori H, Katoh Y, Doi J, Min L, Asano T, et al. Adipose-specific expression, phosphorylation of Ser794 in insulin receptor substrate-1, and activation in diabetic animals of salt-inducible kinase-2. J Biol Chem 2003; 278(20): 18440-7. google scholar
  • 18. Zhang ZN, Gong L, Lv S, Li J, Tai X, Cao W, et al. SIK2 regulates fasting-induced PPARa activity and ketogenesis through p300. Scİ Rep 2016; 6(1): 23317. google scholar
  • 19. Sakamaki JI, Fu A, Reeks C, Baird S, Depatie C, Al Azzabi M, et al. Role of the SIK2-p35-PJA2 complex in pancreatic fj-cell functional compensation. Nat Celi Biol 2014; 16(3): 234-44. google scholar
  • 20. Zohrap N, Saatci Ö, Ozes B, Coban I, Atay HM, Battaloglu E, et al. SIK2 attenuates proliferation and survival of breast cancer cells with simultaneous perturbation of MAPK and PI3K/Akt pathways. Oncotarget 2018; 9(31): 21876-92. google scholar
  • 21. Miranda F, Mannion D, Liu S, Zheng Y, Mangala LS, Redondo C, et al. Salt-inducible kinase 2 couples ovarian cancer cell metabolism with survival at the adipocyte-rich metastatic niche. Cancer Cell 2016; 30(2): 273-89. google scholar
  • 22. Sasaki T, Takemori H, Yagita Y, Terasaki Y, Uebi T, Horike N, et al. SIK2 is a key regulator for neuronal survival after ischemia via TORC1-CREB. Neuron 2011; 69(1): 106-19. google scholar
  • 23. Küser-Abali G, Ozcan F, Ugurlu A, Uysal A, Fuss SH, Bugra-Bilge K. SIK2 is involved in the negative modulation of insulin-dependent Müller cell survival and implicated in hyperglycemia-induced cell death. Invest Ophthalmol Vis Sci 2013; 54(5): 3526. google scholar
  • 24. Kuser-Abali G, Ugurlu-Bayarslan A, Yilmaz Y, Ozcan F, Karaer F, Bugra K. SIK2: A novel negative feedback regulator of FGF signaling. Adv Biology 2024; 8(11): 240003. google scholar
  • 25. Goldman D. Müller glial cell reprogramming and retina regeneration. Nat Rev Neurosci 2014; 15(7): 431-42. google scholar
  • 26. Hollborn M, Jahn K, Limb GA, Kohen L, Wiedemann P, Bringmann A. Characterization of the basic fibroblast growth factor-evoked proliferation of the human Müller cell line, MIO-M1. Graefes Arch Clin Exp Ophthalmol 2004; 242(5): 414-22. google scholar
  • 27. Luo H, Jin K, Xie Z, Qiu F, Li S, Zou M, et al. Forkhead box N4 (Foxn4) activates Dll4-Notch signaling to suppress photoreceptor cell fates of early retinal progenitors. Proc Natl Acad Sci U S A 2012; 109(9): E553-62. google scholar
  • 28. Quintero H, Gömez-Montalvo Al, Lamas M. MicroRNA changes through Müller glia dedifferentiation and early/late rod photoreceptor differentiation. Neurosci 2016; 316: 109-21. google scholar
  • 29. Katsman D, Stackpole EJ, Domin DR, Farber DB. Embryonic stem cell-derived microvesicles induce gene expression changes in Müller cells of the retina. PLoS One 2012; 7(11): e50417. google scholar
  • 30. Tao Z, Zhao C, Jian Q, Gillies M, Xu H, Yin ZQ. Lin28B promotes Müller glial cell de-differentiation and proliferation in the regenerative rat retinas. Oncotarget 2016; 7(31): 49368-83. google scholar
Year 2025, Volume: 15 Issue: 1, 23 - 30, 16.04.2025
https://doi.org/10.26650/experimed.1536826

Abstract

Project Number

Bogazici University Research Projects (8921), TÜBİTAK (113Z108), ÖYP (2012K120490)

References

  • 1. Vecino E, Rodriguez FD, Ruzafa N, Pereiro X, Sharma SC. Glia-neuron interactions in the mammalian retina. Prog Retin Eye Res 2016; 51: 1-40. google scholar
  • 2. Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov S, et al. Müller cells in the healthy and diseased retina. Prog Retin Eye Res 2006; 25(4): 397-424. google scholar
  • 3. Frasson M, Picaud S, Leveillard T, Simonutti M, Mohand-Said S, Dreyfus H, et al. Glial cell line-derived neurotrophic factor induces histologic and functional protection of rod photoreceptors in the rd/rd mouse. İnvest Ophthalmol Vis Sci 1999; 40(11): 2724-34. google scholar
  • 4. Honjo M, Tanihara H, Kido N, İnatani M, Okazaki K, Honda Y. Expression of ciliary neurotrophic factor activated by retinal Müller cells in eyes with NMDA-and kainic acid-induced neuronal death. İnvest Ophthalmol Vis Sci 2000; 41(2): 552-60. google scholar
  • 5. Takeda M, Takamiya A, Yoshida A, Kiyama H. Extracellular signal-regulated kinase activation predominantly in Müller cells of retina with endotoxin-induced uveitis. Invest Ophthalmol Vis Scİ 2002; 43(4): 907-11. google scholar
  • 6. Tezel G, Chauhan BC, LeBlanc RP, Wax MB. Immunohistochemical assessment of the glial mitogen-activated protein kinase activation in glaucoma. Invest Ophthalmol Vis Sci 2003; 44(7): 3025-33. google scholar
  • 7. Dyer MA, Cepko CL. Control of Müller glial cell proliferation and activation following retinal injury. Nat Neurosci 2000; 3(9): 873-80. google scholar
  • 8. Bernardos RL, Barthel LK, Meyers JR, Raymond PA. Late-stage neuronal progenitors in the retina are radial Müller glia that function as retinal stem cells. J Neurosci 2007; 27(26): 7028-40. google scholar
  • 9. Fischer AJ, Reh TA. Müller glia are a potential source of neural regeneration in the postnatal chicken retina. Nat Neurosci 2001; 4(3): 247-52. google scholar
  • 10. Karl MO, Reh TA. Regenerative medicine for retinal diseases: activating endogenous repair mechanisms. Trends Mol Med 2010; 16(4): 193-202. google scholar
  • 11. Hamon A, Roger JE, Yang XJ, Perron M. Müller glial cell-dependent regeneration of the neural retina: An overview across vertebrate model systems. Dev Dyn 2016; 245(7): 727-38. google scholar
  • 12. Limb GA, Salt TE, Munro PMG, Moss SE, Khaw PT. In vitro characterization of a spontaneously immortalized human Müller cell line (MIO-M1). Invest Ophthalmol Vis Sci 2002; 43(3): 864-9. google scholar
  • 13. Lawrence JM, Singhal S, Bhatia B, Keegan DJ, Reh TA, Luthert PJ, et al. MIO-M1 cells and similar muller glial cell lines derived from adult human retina exhibit neural stem cell characteristics. Stem Cells 2007; 25(8): 2033-43. google scholar
  • 14. Bhatia B, Jayaram H, Singhal S, Jones MF, Limb GA. Differences between the neurogenic and proliferative abilities of Müller glia with stem cell characteristics and the ciliary epithelium from the adult human eye. Exp Eye Res 2011; 93(6): 852-61. google scholar
  • 15. Fischer AJ, McGuire CR, Dierks BD, Reh TA. Insulin and fibroblast growth factor 2 activate a neurogenic program in Müller glia of the chicken retina. J Neurosci 2002; 22(21): 9387-98. google scholar
  • 16. Fischer AJ, Scott MA, Tuten W. Mitogen-activated protein kinase-signaling stimulates Müller glia to proliferate in acutely damaged chicken retina. Glia 2009; 57(2): 166-81. google scholar
  • 17. Horike N, Takemori H, Katoh Y, Doi J, Min L, Asano T, et al. Adipose-specific expression, phosphorylation of Ser794 in insulin receptor substrate-1, and activation in diabetic animals of salt-inducible kinase-2. J Biol Chem 2003; 278(20): 18440-7. google scholar
  • 18. Zhang ZN, Gong L, Lv S, Li J, Tai X, Cao W, et al. SIK2 regulates fasting-induced PPARa activity and ketogenesis through p300. Scİ Rep 2016; 6(1): 23317. google scholar
  • 19. Sakamaki JI, Fu A, Reeks C, Baird S, Depatie C, Al Azzabi M, et al. Role of the SIK2-p35-PJA2 complex in pancreatic fj-cell functional compensation. Nat Celi Biol 2014; 16(3): 234-44. google scholar
  • 20. Zohrap N, Saatci Ö, Ozes B, Coban I, Atay HM, Battaloglu E, et al. SIK2 attenuates proliferation and survival of breast cancer cells with simultaneous perturbation of MAPK and PI3K/Akt pathways. Oncotarget 2018; 9(31): 21876-92. google scholar
  • 21. Miranda F, Mannion D, Liu S, Zheng Y, Mangala LS, Redondo C, et al. Salt-inducible kinase 2 couples ovarian cancer cell metabolism with survival at the adipocyte-rich metastatic niche. Cancer Cell 2016; 30(2): 273-89. google scholar
  • 22. Sasaki T, Takemori H, Yagita Y, Terasaki Y, Uebi T, Horike N, et al. SIK2 is a key regulator for neuronal survival after ischemia via TORC1-CREB. Neuron 2011; 69(1): 106-19. google scholar
  • 23. Küser-Abali G, Ozcan F, Ugurlu A, Uysal A, Fuss SH, Bugra-Bilge K. SIK2 is involved in the negative modulation of insulin-dependent Müller cell survival and implicated in hyperglycemia-induced cell death. Invest Ophthalmol Vis Sci 2013; 54(5): 3526. google scholar
  • 24. Kuser-Abali G, Ugurlu-Bayarslan A, Yilmaz Y, Ozcan F, Karaer F, Bugra K. SIK2: A novel negative feedback regulator of FGF signaling. Adv Biology 2024; 8(11): 240003. google scholar
  • 25. Goldman D. Müller glial cell reprogramming and retina regeneration. Nat Rev Neurosci 2014; 15(7): 431-42. google scholar
  • 26. Hollborn M, Jahn K, Limb GA, Kohen L, Wiedemann P, Bringmann A. Characterization of the basic fibroblast growth factor-evoked proliferation of the human Müller cell line, MIO-M1. Graefes Arch Clin Exp Ophthalmol 2004; 242(5): 414-22. google scholar
  • 27. Luo H, Jin K, Xie Z, Qiu F, Li S, Zou M, et al. Forkhead box N4 (Foxn4) activates Dll4-Notch signaling to suppress photoreceptor cell fates of early retinal progenitors. Proc Natl Acad Sci U S A 2012; 109(9): E553-62. google scholar
  • 28. Quintero H, Gömez-Montalvo Al, Lamas M. MicroRNA changes through Müller glia dedifferentiation and early/late rod photoreceptor differentiation. Neurosci 2016; 316: 109-21. google scholar
  • 29. Katsman D, Stackpole EJ, Domin DR, Farber DB. Embryonic stem cell-derived microvesicles induce gene expression changes in Müller cells of the retina. PLoS One 2012; 7(11): e50417. google scholar
  • 30. Tao Z, Zhao C, Jian Q, Gillies M, Xu H, Yin ZQ. Lin28B promotes Müller glial cell de-differentiation and proliferation in the regenerative rat retinas. Oncotarget 2016; 7(31): 49368-83. google scholar
There are 30 citations in total.

Details

Primary Language English
Subjects Clinical Sciences (Other)
Journal Section Research Article
Authors

Aslı Uğurlu Bayarslan 0000-0003-2131-2823

Kuyaş Buğra 0000-0003-1327-5938

Project Number Bogazici University Research Projects (8921), TÜBİTAK (113Z108), ÖYP (2012K120490)
Publication Date April 16, 2025
Submission Date August 23, 2024
Acceptance Date January 6, 2025
Published in Issue Year 2025 Volume: 15 Issue: 1

Cite

Vancouver Uğurlu Bayarslan A, Buğra K. Overexpression of SIK2 Inhibits FGF2-dependent Müller Glial Reprogramming. Experimed. 2025;15(1):23-30.