news and views ity for a series of different orientations in the assumes that there are no intrinsic places in Nigel W. Daw is in the Department of same animal allowed Bonhoeffer and Grin- the cortex that would attract the formation Ophthalmology and Visual Science, Yale University vald6 (using intrinsic signals of activity from of pinwheels. This has been suggested as a School of Medicine, 330 Cedar Street, New Haven, upper layers of cortex7) to show that the factor in positioning of the blobs for colour Connecticut 06520-8061, USA. pinwheel model is correct. in the macaque visual cortex10. e-mail: [email protected] There are many models of how the cortex Wolf and Geisel have used mathematical 1. Wolf, F. & Geisel, T. Nature 395, 73–78 (1998). develops to achieve this pattern8. Cats and approaches that are common in physics but 2. Mountcastle, V. B. J. Neurophysiol. 20, 408–434 (1957). 3. Hubel, D. H. & Wiesel, T. N. J. Physiol. (Lond.) 160, 106–154 macaques show a pattern of orientation rare in biology. In turbulent flow, for exam- (1962). selectivity as soon as the eyes open shortly ple, aspects of a system’s behaviour can be 4. Hubel, D. H. & Wiesel, T. N. J. Comp. Neurol. 158, 267–294 after (or at) birth. But ferrets, which are born predicted from basic symmetries without (1974). 5. Braitenberg, V. & Braitenberg, C. Biol. Cybern. 33, 179–188 8 at an earlier stage of development, show little knowing the detailed nature of the interac- (1979). orientation selectivity when their eyes open. tions between components of the system. 6. Bonhoeffer, T. & Grinvald, A. Nature 353, 429–431 (1991). Instead, orientation selectivity develops to Because the nervous system is made up of 7. Grinvald, A., Lieke, E. E., Frostig, R. D., Gilbert, C. D. & Wiesel, T. N. Nature 324, 361–364 (1986). adult levels during the fifth and sixth weeks billions of cells and trillions of synapses, with 8. Erwin, E., Obermayer, K. & Schulten, K. Neural Comp. 7, after birth, under the influence of nerve-cell detailed interactions that are unknowable 425–468 (1995). activity9. in practice, mathematical approaches may 9. Chapman, B., Stryker, M. P. & Bonhoeffer, T. J. Neurosci. 16, 1 6443–6453 (1996). Wolf and Geisel now suggest that all have a future in predicting the overall behav- 10.Kuljis, R. O. & Rakic, P. Proc. Natl Acad. Sci. USA 87, 5303–5306 models for the development of orientation iour of the system. (1990). selectivity are subject to symmetry princi- ples. The authors first assume that columns RNA processing with a similar orientation preference tend to be a particular distance apart. Their second A tale of two tails assumption is that patterns resulting from (i) David Bentley shifting the pattern parallel to the cortical surface; (ii) rotating the pattern parallel to the cortical surface; and (iii) shifting all ori- he fate of RNAs in the nucleus is deter- sequence YSPTSPS, found at the carboxy entation preferences by the same angle, will mined by the polymerase that made terminus of the pol II large subunit — are arise with the same probability. Their final them. For example, the same primary not efficiently capped, spliced or cleaved at T 4,5 assumption is that the pattern arises from transcript that will give rise to a messenger the poly(A) site . This suggests that the many random factors, and that Gaussian RNA if made by RNA polymerase II (pol II), CTD helps to target mRNA processing fac- statistics apply. Their mathematics then will never mature if is made by pol I, pol III tors to pol II transcripts6,7. Hirose and Man- shows that the expected density of pin- or a bacteriophage RNA polymerase1,2. How ley have now discovered that the CTD facili- wheels is given by can we explain this link between the tates the 38 RNA cleavage reaction, even in ρ = π(1+α) machines that make and process mRNAs? the absence of transcription. They suggest 3 8 L2 On page 93 of this issue, Hirose and Manley that, in effect, the CTD is a cofactor for 3 bring us one step closer to an answer. They processing. where L is the average spacing of columns, report that the carboxy-terminal domain Production of a mature mRNA 38 end and a is a number that describes the struc- (CTD) — a protein domain unique to pol II can be reconstituted in vitro with cleavage/ ture of spatial correlations. One therefore — acts as part of the protein complex that polyadenylation specificity factor (CPSF), expects to find at least p pinwheels in an area fashions the 38 end of the mature mRNA by cleavage-stimulation factor (CstF), cleav- of size L2. cleavage and polyadenylation. age factors CFI and CFII, and poly(A)poly- In fact, the density of pinwheels varies The formation of 38 ends is a two-step merase (PAP)8. The association of CPSF from 3.75 in an area of size L2 in macaque, to process in which the RNA transcript is and CstF with the CTD in vitro4, and the 2.1–2.6 in tree shrew, with intermediate val- cleaved downstream of the sequence colocalization of CstF and phosphorylated ues for squirrel monkey, ferret and cat. Thus, AAUAAA, then a poly(A) tail is added at the pol II in vivo (Fig. 1), indicate that a stable either there is some process that prevents cut end. RNAs made in vivo by pol II lacking ‘mRNA factory’ complex of pol II with pro- development from being carried to comple- the CTD — a conserved repeat of the cessing factors carries out synthesis and tion in the cat and tree shrew, where the value is substantially below p, or the density of Figure 1 Colocalization of the pinwheels develops to a value greater than p, cleavage-stimulation factor then decreases through annihilation of pin- CstF and phosphorylated RNA wheels. Wolf and Geisel propose that such an polymerase II (pol II). annihilation could occur through melding Immunofluorescence of of a pair of pinwheels — one with clockwise Drosophila polytene chirality and another with anticlockwise chromosomes with anti-pol II chirality. monoclonal antibody (left) The annihilation of pinwheels is an and rabbit antibody against intriguing possibility. But it is not supported Suppressor of forked, the by the few observations available, which Drosophila homologue of CstF show a series of orientation maps that does (right). (Courtesy of M. Sikes not change much with age8. Areas with and A. Beyer, University of longer stretches of parallel slabs — which are Virginia.) predicted to arise when two pinwheels merge — do not seem to appear much more fre- quently in the older patterns. So, Wolf and Geisel’s predictions still need to be rigorous- ly tested. Moreover, the mathematics NATURE | VOL 395 | 3 SEPTEMBER 1998 21 Nature © Macmillan Publishers Ltd 1998 news and views Figure 2 Model for activation of Daedalus 38 processing by the pol II PAP carboxy-terminal domain Zero-tolerance policing Pol II (CTD). Hirose and Manley3 have CPSF shown that the CTD is part of Millions of potentially lethal cell Pol II the protein complex that carries mutations occur in each of us every day. P out cleavage and We notice nothing; the immune system - C CstF D TD- polyadenylation to produce a arrests and executes the offenders T P C CPSF mature messenger RNA instantly. But with advancing age, its CF II AAUAAA CstFG/U 5' transcript. CPSF, vigilance slackens. Mutations start to go 8 CF II CF I cleavage/polyadenylation unchecked; and we succumb to the CF I PAP specificity factor; CstF, cleavage- melancholy neoplastic or degenerative 5' AAUAAA G/U stimulation factor; CFI, cleavage diseases of old age. factor I; CFII, cleavage factor II; So Daedalus is extending his scheme of PAP, poly(A)polymerase. last week for priming the immune system against all normal biological proteins. He maturation of the primary transcript9. to this model, which is more consistent with now wants to prime it against abnormal Hirose and Manley provide an insight the effect of creatine phosphate, the CTD proteins as well — in particular, the into how the mRNA factory operates. They behaves as a cofactor or allosteric activator. abnormal ones expressed on the surfaces followed up the curious observation that, in One possible target for allosteric activation is of malfunctioning human cells. a purified system, cleavage at the poly(A) site CstF, which binds the CTD in vitro4. The DREADCO volunteers are now providing is stimulated by creatine phosphate and by importance of this interaction for scaffold- small biopsy tissue samples of blood, lung, phosphoamino acids. They reasoned that ing or allosteric activation could be tested gut, and so on, to be cultured in the usual these compounds may mimic a phospho- using CTD mutants that do not bind CstF. way. The cultures will then be attacked protein that allosterically activates the cleav- It is now clear that pol II stimulates 38 with mutagens, ultraviolet light, X-rays, age reaction. An attractive candidate phos- processing, both in vivo and in vitro, through and such, to induce as many mutations in phoprotein is pol II — the CTD undergoes a the CTD. Conversely, poly(A) factors may them as possible. The battered and cycle of hyperphosphorylation and dephos- affect pol II by influencing the decision to misfiring cells will express all sorts of crazy phorylation (mainly at residues two and five terminate or elongate the RNA chain. Termi- and altered proteins on their surfaces. of the YSPTSPS repeat10) as pol II cycles nation depends on transcription of the These will be extracted, and injected back through transcriptional initiation, elonga- poly(A) signal11, poly(A) factors12 and the into the volunteer from whom the cells tion and termination.