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TGF-β signaling protects retinal neurons from programmed cell death during the development of the mammalian eye
Barbara M Braunger1, Stefan Pielmeier, Cora Demmer
1Institute of Human Anatomy and Embryology, University of Regensburg, D-93053 Regensburg, Germany.
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.
Insights
Transforming growth factor-β (TGF-β) signaling protects retinal neurons from programmed cell death during development. Inhibiting TGF-β signaling increases cell death, while enhancing it promotes neuron survival via nerve growth factor (NGF).
Area of Science:
- Neuroscience
- Developmental Biology
- Cell Biology
Background:
- Transforming growth factor-β (TGF-β) signaling plays a critical role in cellular processes.
- Programmed cell death (apoptosis) is essential for proper tissue development, including the retina.
- The precise role of TGF-β in regulating retinal developmental cell death requires further elucidation.
Purpose of the Study:
- To investigate the influence of TGF-β signaling on programmed cell death in mouse retinal development.
- To determine the molecular mechanisms by which TGF-β affects retinal neuron survival and apoptosis.
- To assess the functional consequences of altered TGF-β signaling on retinal neuron populations.
Main Methods:
- Conditional deletion of TGF-β type II receptor (TβRII) in retinal progenitor cells.
- Conditional deletion of Smad7, a TGF-β inhibitor, in retinal neurons.
- Analysis of phosphorylated Smad3 levels to assess TGF-β pathway activity.
- Assessment of apoptosis using cell death markers.
- Evaluation of neuron numbers in adult mice.
- Functional assessment using electroretinography.
- Measurement of nerve growth factor (NGF) mRNA levels.
Main Results:
- TβRII deficiency in retinal progenitor cells significantly decreased TGF-β signaling activity.
- TβRII deficiency led to increased apoptotic death of retinal neurons during development, reducing adult neuron numbers and causing functional deficits.
- TGF-β2 treatment inhibited retinal ganglion cell death in vitro, an effect blocked by Smad3 inhibition.
- Smad7 deficiency enhanced TGF-β signaling, significantly decreasing apoptosis and increasing retinal neuron numbers.
- TβRII-deficient mice had lower NGF mRNA levels, while Smad7-deficient mice had higher NGF mRNA levels.
Conclusions:
- TGF-β signaling exerts a protective effect against developmental programmed cell death in the mouse retina.
- The neuroprotective role of TGF-β signaling in retinal development is mediated through nerve growth factor (NGF).
- Modulating TGF-β signaling offers a potential therapeutic avenue for retinal neurodegenerative conditions.
