title: Loss of mTOR signaling affects cone function, cone structure and expression of cone specific proteins without affecting cone survival.
abstract: Cones are the primary photoreceptor (PR) cells responsible for vision in humans. They are metabolically highly active requiring phosphoinositide 3-kinase (PI3K) activity for long-term survival. One of the downstream targets of PI3K is the kinase mammalian target of rapamycin (mTOR), which is a key regulator of cell metabolism and growth, integrating nutrient availability and growth factor signals. Both PI3K and mTOR are part of the insulin/mTOR signaling pathway, however if mTOR is required for long-term PR survival remains unknown. This is of particular interest since deregulation of this pathway in diabetes results in reduced PR function before the onset of any clinical signs of diabetic retinopathy. mTOR is found in two distinct complexes (mTORC1 & mTORC2) that are characterized by their unique accessory proteins RAPTOR and RICTOR respectively. mTORC1 regulates mainly cell metabolism in response to nutrient availability and growth factor signals, while mTORC2 regulates pro-survival mechanisms in response to growth factors. Here we analyze the effect on cones of loss of mTORC1, mTORC2 and simultaneous loss of mTORC1 & mTORC2. Interestingly, neither loss of mTORC1 nor mTORC2 affects cone function or survival at one year of age. However, outer and inner segment morphology is affected upon loss of either complex. In contrast, concurrent loss of mTORC1 and mTORC2 leads to a reduction in cone function without affecting cone viability. The data indicates that PI3K mediated pro-survival signals diverge upstream of both mTOR complexes in cones, suggesting that they are independent of mTOR activity. Furthermore, the data may help explain why PR function is reduced in diabetes, which can lead to deregulation of both mTOR complexes simultaneously. Finally, although mTOR is a key regulator of cell metabolism, and PRs are metabolically highly active, the data suggests that the role of mTOR in regulating the metabolic transcriptome in healthy cones is minimal.
authors.affiliation: Tianjin Medical University Eye Hospital, No. 251 Fu Kang Road, Nankai District, Tianjin 300384, PR China; Department of Ophthalmology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA. Electronic address: Shan.Ma@umassmed.edu.
authors.forename: Shan
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Ophthalmology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA. Electronic address: Aditya.Venkatesh@umassmed.edu.
authors.forename: Aditya
authors.initials: A
authors.lastname: Venkatesh
authors.affiliation: Department of Ophthalmology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA. Electronic address: Fernanda.Langellotto@childrens.harvard.edu.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Langellotto
authors.affiliation: Department of Medicine Endocrinology, University of Oklahoma Health Sciences Center, BSEB 302G, 941 S L Young Blvd., Oklahoma City 73104, USA. Electronic address: Yun-Le@ouhsc.edu.
authors.forename: Yun Z
authors.initials: YZ
authors.lastname: Le
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland. Electronic address: m.hall@unibas.ch.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland. Electronic address: markus-a.ruegg@unibas.ch.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
authors.affiliation: Department of Ophthalmology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA. Electronic address: Claudio.Punzo@umassmed.edu.
authors.forename: Claudio
authors.initials: C
authors.lastname: Punzo
mesh_terms: D000818:Animals; D002470:Cell Survival; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D004596:Electroretinography; D005136:Eye Proteins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D005136:Eye Proteins; D007166:Immunosuppressive Agents; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases
keywords: Cone survival; Diabetic retinopathy; Neuroprotective; PI3K; Photoreceptors; Retinitis pigmentosa; Visual function; mTOR