title: TGF-β signaling protects retinal neurons from programmed cell death during the development of the mammalian eye.
abstract: We investigated the influence of transforming growth factor-β (TGF-β) signaling on developmental programmed cell death in the mouse retina by direct and specific molecular targeting of TGF-β type II receptor (TβRII) and Smad7 in retinal progenitor cells. Mice were generated carrying a conditional deletion of the TβRII in cells that originate from the inner layer of the optic cup. The animals showed a significant decrease of phosphorylated Smad3 in both the central and peripheral retina, which indicates the diminished activity of TGF-β signaling. TβRII deficiency significantly increased the apoptotic death of retinal neurons during embryonic and postnatal development without affecting their proliferation. In contrast, treatment with TGF-β2 inhibited cell death of retinal ganglion cells in dissociated retinal cell cultures, an effect that was blocked by inhibiting the phosphorylation of Smad3. The increase in apoptosis during development resulted in a significant reduction in the number of neurons in adult TβRII-deficient mice. The effect was most pronounced in the inner retina neurons and resulted in functional deficits as determined by electroretinography. In contrast, a conditional deletion of TGF-β-inhibiting Smad7 in retinal neurons significantly enhanced Smad3 phosphorylation and significantly decreased apoptosis of retinal neurons in embryos and pups. Moreover, the number of retinal ganglion cells was significantly higher in Smad7-deficient mice compared with control littermates. TβRII-deficient pups showed a lower level of nerve growth factor (NGF) in its mRNA; however, higher levels were observed in Smad7-deficient pups, which strongly suggests that the protective effects of TGF-β signaling on developmental cell death are mediated through NGF.
authors.affiliation: Institute of Human Anatomy and Embryology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Braunger
authors.forename: Stefan
authors.initials: S
authors.lastname: Pielmeier
authors.forename: Cora
authors.initials: C
authors.lastname: Demmer
authors.forename: Victoria
authors.initials: V
authors.lastname: Landstorfer
authors.forename: Daniela
authors.initials: D
authors.lastname: Kawall
authors.forename: Natalie
authors.initials: N
authors.lastname: Abramov
authors.forename: Marco
authors.initials: M
authors.lastname: Leibinger
authors.forename: Ingo
authors.initials: I
authors.lastname: Kleiter
authors.forename: Dietmar
authors.initials: D
authors.lastname: Fischer
authors.forename: Herbert
authors.initials: H
authors.lastname: Jägle
authors.forename: Ernst R
authors.initials: ER
authors.lastname: Tamm
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004622:Embryo, Mammalian; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D055351:Retinal Neurons / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta; D020932:Nerve Growth Factor; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II