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Postnatal in the Human Forebrain: From Two Migratory Streams to Dribbles

Zhengang Yang,1,* Guo-li Ming,2,3,4 and Hongjun Song2,3,4,* 1Institutes of Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032, China 2Institute for Cell Engineering 3Department of Neurology 4The Solomon H. Snyder Department of Neuroscience Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA *Correspondence: [email protected] (Z.Y.), [email protected] (H.S.) DOI 10.1016/j.stem.2011.10.007

Subventricular zone neurogenesis occurs throughout life from rodents to primates, but the existence of a of immature in postnatal human is controversial. A recent report in Nature (Sanai et al., 2011) identifies two neuronal migratory streams in infant human brains targeting the and prefrontal cortex.

Almost all mammalian species examined lateral ventricle to the olfactory bulb, one other recent study (Wang et al., exhibit continuous neurogenesis in spe- based on expression of PCNA, PSA- 2011), do not report a persistent ventric- cific brain regions, and cumulative evi- NCAM, and bIII- (Curtis et al., ular lumen connecting the adult human dence supports critical roles for newborn 2007). lateral ventricle to the olfactory bulb, neurons in brain functions, including In a collaborative effort between stem although this structure appears to exist learning, , and mood regulation cell biologists, neuropathologists, and in the fetal human brain (Guerrero-Ca´ - (Ming and Song, 2011). Two neurogenic neurosurgeons, Sanai et al. (2011) aimed zares et al., 2011; Wang et al., 2011). regions in the adult brain have been firmly to clarify and comprehensively charac- Interestingly, Sanai et al. (2011) also established in species from rodents to terize the landscape of neurogenesis in describe the absence of this ventricular primates. In the of the the human SVZ by examining extension in the postnatal infant human , neural stem cells produce proliferation and migratory patterns in 60 brain as well. Taken together with more local glutamatergic dentate granule neu- postmortem human brain specimens recent studies (Guerrero-Ca´ zares et al., rons. In the (SVZ), ranging in age from birth to 84 years. First, 2011; Wang et al., 2011), these findings radial glia-like neural stem cells give rise Sanai and colleagues analyzed the distri- by Sanai et al. (2011) implicate dynamic to that migrate through bution of putative immature migrating changes in human SVZ neurogenesis the rostral migratory stream (RMS) into neurons in the SVZ of the anterior horn across the lifespan; proliferation and mi- the olfactory bulb to become mostly of the lateral ventricle and RMS in the gration of immature SVZ and RMS neu- GABAergic of different infant human brain. They found many rons, although robust during infancy, subtypes. In humans, postnatal dentate elongated unipolar and bipolar cells that occur in the absence of persistent ventric- neurogenesis has been shown to occur express immature neuronal markers ular extension and exhibit precipitous across the lifespan (Eriksson et al., 1998; DCX, bIII-tubulin, and PSA-NCAM in the postnatal decline into adulthood. Knoth et al., 2010). In contrast, the pres- SVZ and RMS (Figure 1A), which is One exciting novel finding from Sanai ence of prominent neurogenesis and an consistent with recent findings from fetal et al. (2011) is the identification of a sec- RMS in the adult human SVZ has been human brains (Guerrero-Ca´ zares et al., ond route, the medial migratory stream under debate (Curtis et al., 2007; Sanai 2011; Wang et al., 2011). They observed (MMS; Figure 1A) of neuroblasts targeting et al., 2004). In 2004, Sanai and col- many proliferating Ki67+ cells in the SVZ, the ventromedial prefrontal cortex leagues reported the presence of a rib- some of which were also DCX+ or PSA- (VMPFC) in human specimens age bon of in the adult human NCAM+. Importantly, the numbers of 4–6 months, but not age 8–18 months. SVZ that function as multipotent neural proliferating cells and migrating neuro- The MMS contains a large number of stem cells in culture (Sanai et al., 2004). blasts in the human SVZ and RMS de- migrating neuroblasts, some of which They found, however, only a few prolifer- crease drastically from birth to 18 months express markers calretinin ating cells and putative migratory bIII- of age. In adult human brains, Sanai et al. and tyrosine hydroxylase. These imma- tubulin+ immature neurons, and no evi- (2011) noted very few putative migrating ture interneurons were also found in a dence of chains of migrating neuroblasts neuroblasts in the same regions (Fig- restricted subregion of the VMPFC but in the SVZ or RMS to the olfactory bulb. ure 1B), consistent with a recent report were largely absent in adjacent prefrontal In contrast, Curtis and colleagues (2007) on immature neurons in the adult SVZ areas. In contrast, Sanai et al. (2011) did reported robust cell proliferation in adult and RMS-like pathway (the remnant of not observe a robust MMS in postnatal human SVZ and the presence of a migra- the infant RMS) (Wang et al., 2011). Con- mice but only individual DCX+ cells mi- tory stream of neuroblasts along a lateral trary to previous findings (Curtis et al., grating ventrally and laterally that might ventricular extension that connects the 2007), Sanai and colleagues, as well as target analogous regions. A previous

Cell Stem Cell 9, November 4, 2011 ª2011 Elsevier Inc. 385 Cell Stem Cell Previews

study employing transgenic mice directly. With the development of expressing EGFP in 5-HT3aR+ better tools and a collaborative neurons revealed a much more spirit, the best chapters for postnatal widespread migration of different human neurogenesis research are types of GABAergic immature yet to come. neurons from juvenile postnatal SVZ into numerous forebrain structures, REFERENCES including the prefrontal cortex, although a distinct migratory stream Curtis, M.A., Kam, M., Nannmark, U., was not evident (Inta et al., 2008). Anderson, M.F., Axell, M.Z., Wikkelso, C., Holta˚ s, S., van Roon-Mom, W.M., Bjo¨ rk- These exciting new findings Eriksson, T., Nordborg, C., et al. (2007). confirm the significant regenerative Science 315, 1243–1249. capacity of postnatal human brains, Eriksson, P.S., Perfilieva, E., Bjo¨ rk- especially during infancy, and reveal Eriksson, T., Alborn, A.M., Nordborg, C., Peterson, D.A., and Gage, F.H. (1998). critical properties of SVZ neurogen- Nat. Med. 4, 1313–1317. esis, including diverse neuronal subtypes, contribution to different Guerrero-Ca´ zares, H., Gonzalez-Perez, O., Soriano-Navarro, M., Zamora-Berridi, G., brain regions and the time course Garcı´a-Verdugo, J.M., and Quinon˜ es- of decline. The substantial contribu- Hinojosa, A. (2011). J. Comp. Neurol. 519, 1165–1180. tion of SVZ neurogenesis to pre- Figure 1. Neurogenesis in the Postnatal Human SVZ Inta, D., Alfonso, J., von Engelhardt, J., frontal cortical circuitry raises the (A) In the infant human brain, a large number of neuroblasts Kreuzberg, M.M., Meyer, A.H., van Hooft, possibility that aberrant postnatal derived from the SVZ migrate not only into the olfactory bulb J.A., and Monyer, H. (2008). Proc. Natl. development of these new neurons (OB) through the rostral migratory stream (RMS), but also Acad. Sci. USA 105, 20994–20999. may be involved in the pathogenesis into the ventromedial prefrontal cortex (VMPFC) through the medial migratory stream (MMS). Knoth, R., Singec, I., Ditter, M., Pantazis, G., of mental disorders, such as schizo- (B) In the adult human brain, only a few migrating neuroblasts in Capetian, P., Meyer, R.P., Horvat, V., Volk, phrenia. These findings may also isolation are present in the SVZ and the remnant RMS. Post- B., and Kempermann, G. (2010). PLoS 5 provide insight into other neonatal natal migration of neuroblasts occurs in the absence of olfac- ONE , e8809. tory ventricular extension. brain diseases, especially those Merkle, F.T., Mirzadeh, Z., and Alvarez- 317 arising from pathology in periven- Buylla, A. (2007). Science , 381–384. tricular structures. In addition, the lack of detailed lineage-tracing, histological char- Ming, G.L., and Song, H. (2011). 70, significant proliferation and the limited acterization, electrophysiological anal- 687–702. number of neural stem cells and progeni- ysis, and, potentially, genetic elimination Sanai, N., Nguyen, T., Ihrie, R.A., Mirzadeh, Z., tors in adult human SVZ may set the limit for behavioral analysis. Second, is there Tsai, H.H., Wong, M., Gupta, N., Berger, M.S., for their contribution to brain tumors. a common precursor for newborn neurons Huang, E., Garcia-Verdugo, J.M., et al. (2011). Nature 478, 382–386. These fascinating findings also raise targeting the olfactory bulb and prefrontal new questions. First, what are the proper- cortex or is early postnatal human SVZ Sanai, N., Tramontin, A.D., Quin˜ ones-Hinojosa, A., ties and function of SVZ-derived neurons prepatterned with precursors of restricted Barbaro, N.M., Gupta, N., Kunwar, S., Lawton, in human prefrontal cortex? More detailed potentials as in rodents (Merkle et al., M.T., McDermott, M.W., Parsa, A.T., Manuel- Garcı´a Verdugo, J., et al. (2004). Nature 427, study in rodents and primates is war- 2007)? Third, what is the mechanism 740–744. ranted, given the observation of robust underlying the rapid decline of neurogene- migrating SVZ-derived new neurons to sis in postnatal human SVZ? As exempli- Wang, C., Liu, F., Liu, Y.Y., Zhao, C.H., You, Y., Wang, L., Zhang, J., Wei, B., Ma, T., Zhang, Q., cortical areas in early postnatal mice (Inta fied by these recent studies, it is very fruit- et al. (2011). Cell Res. Published online May 17, et al., 2008) and the available tools for ful and rewarding to study human systems 2011, 101038/cr201183.

386 Cell Stem Cell 9, November 4, 2011 ª2011 Elsevier Inc.