RESEARCH HIGHLIGHTS

NEURODEGENERATIVE DISORDERS Another piece of the prion puzzle

The prion hypothesis — that spongi- developed neurological disease, form encephalopathies are caused although with a long incubation and transmitted by a misfolded prion period of between 380 and 660 protein — has been accepted for days. Control mice, inoculated with some time, but has not yet been phosphate-buffered saline, did not proved. Now, research published in develop symptoms of neurological Science takes us a step closer to prov- dysfunction after 620 days. ing the infectivity of prion protein. The authors then took prions Legname et al. report that synthetic from the brains of mice infected with mammalian prions cause disease the synthetic prion and transferred when they are transferred to trans- them to transgenic and wild-type genic mice. mice. This resulted in disease in both Legname et al. used Escherichia types of mice, and, although the coli to produce recombinant mouse incubation period was longer in prion protein (recMoPrP), which wild-type mice, the incubation they polymerized into amyloid fibrils, period in all the mice was consider- creating the synthetic prions. ably shorter than that of the mice that Intracerebral injection was used to received the original synthetic prions. administer these synthetic prions Legname et al. point out that to transgenic mice that expressed as the amino-acid sequence used in very high levels of cellular prion pro- creating the synthetic prion did tein (PrPC). The mice subsequently not contain the asparagine-linked

SYNAPTOGENESIS New players in presynaptic organization

One of the most intriguing questions in differentiation in vivo,and they obtained either FGF7 or FGF10, so it seems likely that developmental neuroscience is: how are several lines of evidence to indicate that this it is the main presynaptic organizing growth cones transformed into presynaptic is indeed the case. FGF22 is expressed in molecule, at least in this part of the brain. terminals? Retrograde signals from the cerebellar granule cells at the same time that Through this work, Umemori et al. have postsynaptic cell are believed to be they are being innervated by mossy fibres not only defined a new role for instrumental in this process, and a new study from vestibular and pontine neurons, and, in postsynaptically derived FGFs in from the laboratory of Joshua Sanes has turn, the vestibular and pontine neurons presynaptic assembly, but they have also uncovered an important role for members of express the FGFR2 gene, which codes for the assigned a developmental function to the the fibroblast (FGF) family in main FGF22 receptor FGFR2b. Mossy-fibre FGF7/10/22 subfamily, which has not presynaptic organization. presynaptic differentiation was impaired previously been implicated in neural Umemori et al. prepared an extract from both in vivo and in vitro when FGF22 development. The next step will be to show postnatal day 7 mouse forebrains, and activity was neutralized with a soluble by more direct means that FGF22 induces screened this extract for molecules that could recombinant form of FGFR2b (FGFR2bAP), presynaptic differentiation in vivo,and mice induce clustering of synaptic vesicles in the and conditional deletion of the FGFR2 gene with mutations in the FGF22 gene are neurites of cultured chick motor neurons. in newborn mice produced a similar result. already being generated to test this They purified one of the main components of FGF22 belongs to an FGF subfamily that hypothesis. It will also be interesting to find the extract that promoted vesicle clustering, also includes FGF7 and FGF10. All three out whether FGF7 and FGF10 have similar and identified this component as FGF22. The molecules were shown to promote vesicle roles at other types of synapse. FGF22-induced vesicle clusters underwent clustering in vitro, and all three bind to Heather Wood recycling in response to neuronal FGFR2b and are neutralized by FGFR2bAP. References and links depolarization, implying that FGF22 was Therefore, the authors could not rule out the ORIGINAL RESEARCH PAPER Umemori, H. et al. FGF22 promoting the development of functional possibility that FGF7 and FGF10 were and its close relatives are presynaptic organizing molecules presynaptic structures. responsible for the effects that they observed in the mammalian brain. Cell 118, 257–270 (2004) FURTHER READING Ziv, N. E. & Garner, C. G. Cellular and The authors then went on to investigate in vivo.However, FGF22 is expressed at a molecular mechanisms of presynaptic assembly. Nature Rev. whether FGF22 promotes presynaptic much higher level in the cerebellum than Neurosci. 5, 385–399 (2004)

674 | SEPTEMBER 2004 | VOLUME 5 www.nature.com/reviews/neuro