RESUMEN
We investigated the influence of transforming growth factor-ß (TGF-ß) signaling on developmental programmed cell death in the mouse retina by direct and specific molecular targeting of TGF-ß type II receptor (TßRII) and Smad7 in retinal progenitor cells. Mice were generated carrying a conditional deletion of the TßRII 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-ß signaling. TßRII deficiency significantly increased the apoptotic death of retinal neurons during embryonic and postnatal development without affecting their proliferation. In contrast, treatment with TGF-ß2 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 TßRII-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-ß-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. TßRII-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-ß signaling on developmental cell death are mediated through NGF.
Asunto(s)
Apoptosis , Neuronas Retinianas/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Proliferación Celular , Embrión de Mamíferos , Eliminación de Gen , Regulación del Desarrollo de la Expresión Génica , Ratones , Factor de Crecimiento Nervioso/genética , Factor de Crecimiento Nervioso/metabolismo , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Mensajero/metabolismo , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Neuronas Retinianas/citología , Transducción de Señal , Proteína smad7/genética , Transcripción GenéticaRESUMEN
Similar to other parts of the central nervous system, there are two types of programmed cell death during retinal development. In early development, the neuronal progenitor population is affected. In the mouse eye, this kind of programmed cell death begins at around embryonic day (E) 12.5 and peaks between E14.5 and E16.5. The second phase of programmed cell death occurs during synaptogenesis within the first 2 postnatal weeks. Important signaling mechanisms that induce programmed cell death of retinal progenitors appear to involve nerve growth factor acting on the proapoptotic receptor to p75 neurotrophin receptor (p75(NTR)) and transforming growth factor-ß.