Activin A is essential for neurogenesis following neurodegeneration.

It has long been proposed that excitotoxicity contributes to nerve cell death in neurodegenerative diseases. Activin A, a member of the transforming growth factor-beta superfamily, is expressed by neurons following excitotoxicity. We show for the first time that this activin A expression is essential for neurogenesis to proceed following neurodegeneration. We found that intraventricular infusion of activin A increased the number of newborn neurons in the dentate gyrus, CA3, and CA1 layers of the normal adult hippocampus and also, following lipopolysaccharide administration, had a potent inhibitory effect on gliosis in vivo and on microglial proliferation in vivo and in vitro. Consistent with the role of activin A in regulating central nervous system inflammation and neurogenesis, intraventricular infusion of follistatin, an activin A antagonist, profoundly impaired neurogenesis and increased the number of microglia and reactive astrocytes following onset of kainic acid-induced neurodegeneration. These results show that inhibiting endogenous activin A is permissive for a potent underlying inflammatory response to neurodegeneration. We demonstrate that the anti-inflammatory actions of activin A account for its neurogenic effects following neurodegeneration because co-administration of nonsteroidal anti-inflammatory drugs reversed follistatin's inhibitory effects on neurogenesis in vivo. Our work indicates that activin A, perhaps working in conjunction with other transforming growth factor-beta superfamily molecules, is essential for neurogenesis in the adult central nervous system following excitotoxic neurodegeneration and suggests that neurons can regulate regeneration by suppressing the inflammatory response, a finding with implications for understanding and treating acute and chronic neurodegenerative diseases.

Developmental death of photoreceptors in the C57BL/6J mouse: association with retinal function and self-protection.

We have investigated the relationship between cell death among photoreceptors and the expression of function- and stress-related proteins during the development of the retina of the C57BL/6J mouse. Retinas from mice aged P(postnatal day)4 to P63 (adult) were examined for cell death using the TUNEL technique, and for the expression of basic fibroblast growth factor (bFGF), cytochrome oxidase (CO), rod opsin and glial fibrillary acidic protein (GFAP), using immunocytochemistry. At P4, cell death is most prominent in the inner layers of retina, declining to near-zero levels by P16. Cell death among photoreceptors occurs in a discrete wave commencing at approximately P12 and remaining elevated into the 4th postnatal week, beginning, peaking and declining later than in inner retina. The onset of photoreceptor death correlates with the expression of function-related molecules, such as CO and opsin. The decline in photoreceptor death correlates with the expression of the protective factor bFGF in photoreceptors. At the anterior edge of the retina photoreceptor death and the expression of bFGF are accelerated, and the expression of bFGF and GFAP is upregulated, by an edge-specific stress. We conclude that in the mouse photoreceptors undergo a wave of death which culls the neonatal population to adult levels. The onset of photoreceptor death is related to the acceleration of photoreceptor metabolism and function between P12 and P20. The decline of photoreceptor death to the very low levels found in the adult may be mediated by the upregulation of protective factors such as bFGF. Photoreceptor death and the expression of bFGF and GFAP at the edge of the retina are regulated by a still-unidentified, edge-specific stress, from as early as P16.

Regulation by oxygen of photoreceptor death in the developing and adult C57BL/6J mouse.

We have examined the role of tissue oxygen in the regulation of photoreceptor death in the C57BL/6J mouse. Litters of C57BL/6J mice were raised in dim cyclic (12 hr dark, 12 hr 50 lx) light. Adults or litters aged P7 or P8 were placed with their mothers in plexiglass chambers in which oxygen levels were set at 21% (normoxic), 10 or 11% (hypoxic) or 70% (hyperoxic) for up to 22 days. At intervals after introduction to these chambers, retinas were examined for cell death, using the TUNEL technique. Hypoxia accelerated cell death up to five-fold during a critical developmental period from approximately P12 to 18. Thereafter hypoxia-induced cell death declined rapidly. Hyperoxia slowed photoreceptor death over the same period, to approximately half control levels. At the anterior edge of the developing retina the effects of hypoxia and hyperoxia differed markedly from the rest of the retina. In the adult, hypoxia accelerated photoreceptor death, but the acceleration was an order of magnitude weaker than during the critical period of developing retina. Hypoxia-induced photoreceptor death remained above control levels after 20 days exposure. Results suggest that the naturally occurring wave of photoreceptor death seen in developing mouse retina during their development (P12-P20) is regulated by a physiological episode of hypoxia. After P20, photoreceptor vulnerability to hypoxia falls to a low but significant level. The edge of the retina appears subject to chronic hyperoxic stress from P14 into adulthood. Tissue oxygen levels are important determinants of photoreceptor death and survival in both developing and adult retina.