538 VOLUME 14 | NUMBER 5 | MAY 2011 NATURE NEUROSCIENCE NEWS AND VIEWS 10. Santana, L.F. & Navedo, M.F. J. Gen. Physiol. 136, 143–147 (2010). 11. Jing, L., Lefebvre, J.L., Gordon, L.R. & Granato, M. Neuron 61, 721–733 (2009). 12. Budnik, V. & Salinas, P.C. Curr. Opin. Neurobiol. 21, 151–159 (2011). 13. Rüegg, M.A. & Glass, D.J. Annu. Rev. Pharmacol. Toxicol. 51, 373–395 (2011). 14. Williams, A.H. et al. Science 326, 1549–1554 (2009). 15. Selkoe, D.J. Science 298, 789–791 (2002). 4. Wu, H., Xiong, W.C. & Mei, L. Development 137, 1017–1033 (2010). 5. Yang, X. et al. Neuron 30, 399–410 (2001). 6. Kim, N. & Burden, S.J. Nat. Neurosci. 11, 19–27 (2008). 7. Catterall, W.A. Annu. Rev. Cell Dev. Biol. 16, 521–555 (2000). 8. Piétri-Rouxel, F. et al. EMBO J. 29, 643–654 (2010). 9. Wheeler, D.G., Barrett, C.F., Groth, R.D., Safa, P. & Tsien, R.W. J. Cell Biol. 183, 849–863 (2008). 538 VOLUME 14 | NUMBER 5 | MAY 2011 NATURE NEUROSCIENCE NEWS AND VIEWS NEWS AND VIEWS COMPETING FINANCIAL INTERESTS The author declares competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/natureneuroscience/. 1. Taylor, A.B. & Fallon, J.R. J. Neurosci. 26, 1154–1163 (2006). 2. Sanes, J.R. & Yamagata, M. Annu. Rev. Cell Dev. Biol. 25, 161–195 (2009). 3. Chen, F. et al. Nat. Neurosci. 14, 570–577 (2011). Hanging by the tail: progenitor populations proliferate Zoltán Molnár, Navneet A Vasistha & Fernando Garcia-Moreno A study now identifies a new progenitor subtype in the developing mouse cortex, similar to the outer radial glia progenitors described previously in human, ferret and other mammals with larger, folded brains. Zoltán Molnár, Navneet A. Vasistha and Fernando Garcia-Moreno are in the Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK. e-mail: zoltan.molnar@dpag.ox.ac.uk Readers in touch with this field might remember recent studies showing the presence of a new progenitor subtype in human, ferret and other mammals with expanded, convoluted (gyren- cephalic) cortices: the outer subventricular zone (OSVZ) progenitor 1–3 (called interme- diate radial glia by Reillo et al. 3 ). A new study based on cellular behavior, morphology and gene expression pattern shows that similar progenitors, termed outer radial glia (oRG) or (by Shitamukai et al. 4 ) outer ventricular zone progenitors, reside in the developing mouse cortex 5 . These oRG progenitors lack contact with the ventricular (apical) surface, but they maintain their tail-like pial (basal) processes and thus appear to be ‘hanging’ from the pial surface. They constitute a third population of cortical progenitors, the others being radial glia and intermediate progenitor cells (IPCs) (Fig. 1a). Radial glial cells span the width from ventricular to pial surface, undergoing interki- netic nuclear migration during their cell cycle and finally dividing at the ventricular surface. IPCs are derived from asymmetric divisions of radial glia cells; they express the transcription factor Tbr2 and divide within the subventricu- lar zone without nuclear translocation 6 . The general readership might ask why this topic is so newsworthy. The answer lies in the widespread implications that understanding of cortical progenitor populations has for stem cell biology, cortical neurogenesis, evolution- ary biology and comparative biology—leading toward the ‘holy grail’ that is the comprehen- sion of the expansion of the mammalian cerebral cortex 7 . The Wang et al. paper 5 together with the Shitamukai et al. 4 publication are landmarks because they link the previously identified OSVZ progenitors in the human and ferret to these oRG progenitors in the mouse, thereby not only providing a highly accessible model organism for which detailed quantita- tive cell biological analyses are available, but also reinforcing the concept of a uniform devel- opmental mechanism for all mammals. This entire line of research started with the discovery of cytoarchitectonic distinctions within the germinal zone in macaque and human cortices. Smart et al. 8 described the subventricular zone of the macaque cortex as being subdivided into an inner subven- tricular zone (ISVZ) and outer subventricular zone (OSVZ) by a thin layer of fibers, the inner fiber layer (Fig. 1a). Discovery of three cyto- architectonically distinct germinal zones—the ventricular zone, ISVZ and OSVZ—already emphasized the heterogeneity of the cortical progenitor populations 8,9 , although the mor- phological details of the OSVZ progenitors and their mode of cell division were not fully understood 10 . Initially, the OSVZ compart- ment in human and macaque was considered an expansion of IPCs 11,12 , before gene expres- sion data suggested some similarities with radial glia 10 . Previous studies in human and ferret had revealed the distinct morphology and somal translocation behavior of OSVZ progenitors 1,2 . Besides having a pially directed process and lacking any contact with the ven- tricular surface, these also express progenitor- specific markers such as Sox2 and Pax6 and are negative for the IPC marker Tbr2. Although previous studies had suggested that proliferative cell divisions occur within the upper SVZ in rodent during embryonic development 13 , the human and ferret studies prompted the search for similar cells in the mouse. The oRGs in mouse are less abundant than in primates and do not reside in a cyto- architectonically separate zone 1,5 (Fig. 1a). The Kriegstein group exploited methods of real-time recording to study labeled progenitor neurons in slice cultures and combined these with additional labeling methods 2,6 . They injected GFP-expressing adenovirus or retro- virus into the lateral ventricle or, to label oRGs, injected GFP-expressing adenovirus at the pial surface, and they followed labeled progenitors and their cell divisions for prolonged periods. This approach revealed all three progenitors— oRG, radial glia and IPC—with their distinct patterns of cell division. In addition, the authors electroporated plasmids expressing fluorescent proteins to visualize the nucleus and cell shape. Such studies demonstrated that radial glia progenitors show periods of interki- netic nuclear migration (apical-to-basal move- ment of nuclei in phase with the cell cycle) punctuated by cell divisions at the ventricular surface of the germinal zone 6 . In their latest study, Wang et al. 5 used time- lapse imaging to show that oRG progenitor cells arise from asymmetric divisions of radial glia and undergo self-renewing asymmetric divisions in a horizontal plane to generate a neuron (identified by morphology and from the presence of the neuron-specific mark- ers NeuN and Tuj1). The other daughter cell inherits the basal process and maintains an oRG morphology and Pax6 expression. The authors also provide rare examples of © 2011 Nature America, Inc. All rights reserved.