title: Mammalian STE20-like kinase 2, not kinase 1, mediates photoreceptor cell death during retinal detachment.
abstract: Photoreceptor cell death is the definitive cause of vision loss in retinal detachment (RD). Mammalian STE20-like kinase (MST) is a master regulator of both cell death and proliferation and a critical factor in development and tumorigenesis. However, to date the role of MST in neurodegeneration has not been fully explored. Utilizing MST1(-/-) and MST2(-/-) mice we identified MST2, but not MST1, as a regulator of photoreceptor cell death in a mouse model of RD. MST2(-/-) mice demonstrated significantly decreased photoreceptor cell death and outer nuclear layer (ONL) thinning after RD. Additionally, caspase-3 activation was attenuated in MST2(-/-) mice compared to control mice after RD. The transcription of p53 upregulated modulator of apoptosis (PUMA) and Fas was also reduced in MST2(-/-) mice post-RD. Retinas of MST2(-/-) mice displayed suppressed nuclear relocalization of phosphorylated YAP after RD. Consistent with the reduction of photoreceptor cell death, MST2(-/-) mice showed decreased levels of proinflammatory cytokines such as monocyte chemoattractant protein 1 and interleukin 6 as well as attenuated inflammatory CD11b cell infiltration during the early phase of RD. These results identify MST2, not MST1, as a critical regulator of caspase-mediated photoreceptor cell death in the detached retina and indicate its potential as a future neuroprotection target.
authors.affiliation: Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: H
authors.initials: H
authors.lastname: Matsumoto
authors.affiliation: Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: H
authors.initials: H
authors.lastname: Lin
authors.affiliation: Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Connor
authors.affiliation: Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Miller
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: D
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: J
authors.initials: J
authors.lastname: Avruch
authors.affiliation: Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Vavvas
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020419:Photoreceptor Cells, Vertebrate / Q000201:enzymology* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012163:Retinal Detachment / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000090742:Serine-Threonine Kinase 3; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D053148:Caspase 3; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; D016159:Tumor Suppressor Protein p53; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases; C490818:Stk3 protein, mouse; C505409:Casp3 protein, mouse