A Back Door to Cortical Development
2017; Elsevier BV; Volume: 20; Issue: 3 Linguagem: Inglês
10.1016/j.stem.2017.02.006
ISSN1934-5909
Autores Tópico(s)Pluripotent Stem Cells Research
ResumoThe mammalian cortex develops in an "inside-out" manner, as neural stem and progenitor cells lining the ventricles build the brain from within. Bifari et al., 2017Bifari F. Docimo I. Pino A. Llorens-Babadilla E. Zhao S. Lange C. Panuccio G. Boeckx B. Thienpont B. Vinckier S. et al.Cell Stem Cell. 2017; 20 (this issue): 360-373Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, in this issue of Cell Stem Cell, find a small set of cortical neurons that appear to originate from radial glia-like progenitors in the meninges, suggesting an outside-in contribution to corticogenesis. The mammalian cortex develops in an "inside-out" manner, as neural stem and progenitor cells lining the ventricles build the brain from within. Bifari et al., 2017Bifari F. Docimo I. Pino A. Llorens-Babadilla E. Zhao S. Lange C. Panuccio G. Boeckx B. Thienpont B. Vinckier S. et al.Cell Stem Cell. 2017; 20 (this issue): 360-373Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, in this issue of Cell Stem Cell, find a small set of cortical neurons that appear to originate from radial glia-like progenitors in the meninges, suggesting an outside-in contribution to corticogenesis. Research into development of the mammalian neocortex has recently yielded several surprises. The cortex is characterized by massive neuronal diversity that is thought to be generated in an "inside-out" pattern, as neural stem cell populations that reside near the ventricles of the brain sequentially generate the neurons destined for each cortical layer above. However, like watchmakers who admire complications, neurobiologists specializing in cortical development have been adding complexity to their model. First it was found that neurons, historically regarded as the "noble elements" of the brain, are actually derived from glia-like cells that had generally been considered to only have rather supportive roles in brain development and function (Kriegstein and Alvarez-Buylla, 2009Kriegstein A. Alvarez-Buylla A. Annu. Rev. Neurosci. 2009; 32: 149-184Crossref PubMed Scopus (1631) Google Scholar). Second, the textbook model of cortical layer generation has had to be considerably revised. For instance, the majority of neurons in the large cortices of species with gyrified brains arise from an outer subventricular zone (oSVZ) that had not been recognized in mice or rats, which have smooth cortices (Fietz et al., 2010Fietz S.A. Kelava I. Vogt J. Wilsch-Bräuninger M. Stenzel D. Fish J.L. Corbeil D. Riehn A. Distler W. Nitsch R. Huttner W.B. Nat. Neurosci. 2010; 13: 690-699Crossref PubMed Scopus (573) Google Scholar, Hansen et al., 2010Hansen D.V. Lui J.H. Parker P.R.L. Kriegstein A.R. Nature. 2010; 464: 554-561Crossref PubMed Scopus (898) Google Scholar). While there is still no convincing evidence of continued adult neurogenesis in the mammalian cortex, there are notable questions about how and when different cell types might arise. Generation of specific neuronal populations has been reported at least at relatively early postnatal stages (Dayer et al., 2005Dayer A.G. Cleaver K.M. Abouantoun T. Cameron H.A. J. Cell Biol. 2005; 168: 415-427Crossref PubMed Scopus (371) Google Scholar), and a mysterious class of NG2 cells, a category of glial cells, seem to share some neuronal properties and may be mistaken as new neurons. These wanderers between the worlds of glia and neurons, highly responsive to injury but also to some forms of more physiological activation, highlight serious open questions regarding the architecture of the neocortex and its dynamics, development, and plasticity. Reporting in Cell Stem Cell, Peter Carmeliet and colleagues (Bifari et al., 2017Bifari F. Docimo I. Pino A. Llorens-Babadilla E. Zhao S. Lange C. Panuccio G. Boeckx B. Thienpont B. Vinckier S. et al.Cell Stem Cell. 2017; 20 (this issue): 360-373Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar) add to this complicated picture and show that a population of precursor cells with radial glia-like properties resides in the developing meninges, the exterior lining of the brain and spinal cord, and might contribute neurons to the developing neocortex. By expressing a viral lineage-tracer in meningeal cells, Bifari et al. specifically identified a population of Satb2+ interneurons in layers II to IV in the more rostral parts of the mouse cortex that they suggest arises from such a population. They used additional methods to confirm their finding to the best of their ability, considering that there is no known transgenic driver specific for meningeal populations. The adult neocortex contains numerous populations of interneurons and, reminiscent of insect species, new classes are continuously discovered (Rudy et al., 2011Rudy B. Fishell G. Lee S. Hjerling-Leffler J. Dev. Neurobiol. 2011; 71: 45-61Crossref PubMed Scopus (841) Google Scholar). The ganglionic eminences of the ventral forebrain are the best-characterized source of the three main classes of cortical interneurons, which migrate into the cortical layers perpendicularly to the radial path of the principal neurons. While we know relatively little about the subtle functional differences between the numerous classes of interneurons, we know even less about how exactly they develop and how their development relates to the development of the principal and projection neurons that define the cortical layers. In fact, single-cell RNA-seq profiles of adult cerebral cortex have suggested the existence of molecularly defined clusters of cells that represent types of progenitor cells (Johnson et al., 2015Johnson M.B. Wang P.P. Atabay K.D. Murphy E.A. Doan R.N. Hecht J.L. Walsh C.A. Nat. Neurosci. 2015; 18: 637-646Crossref PubMed Scopus (193) Google Scholar) and neurons (Zeisel et al., 2015Zeisel A. Muñoz-Manchado A.B. Codeluppi S. Lönnerberg P. La Manno G. Juréus A. Marques S. Munguba H. He L. Betsholtz C. et al.Science. 2015; 347: 1138-1142Crossref PubMed Scopus (1754) Google Scholar) that are outside of the conventionally defined populations. This raises further questions about the developmental paths leading to the broad cellular diversity found in the brain. Although the neuronal population described by Bifari et al. has already been generally characterized, its origin now seems truly distinct. The meninges seem to be an unusual site for precursor cells; however, through the perivascular, so-called Virchow-Robin spaces they reach far into the brain parenchyma. The meningeal neurogenic precursors are PDGFRβ+ and display molecular, though not morphological, characteristics of radial glia, which Bifari and colleagues confirmed with the help of single-cell transcriptomics. Intriguingly, expression of PDGFRβ suggests a relationship to pericytes, another rather enigmatic class of cells of the brain with relevance to plasticity and repair, and also scarring (Göritz et al., 2011Göritz C. Dias D.O. Tomilin N. Barbacid M. Shupliakov O. Frisén J. Science. 2011; 333: 238-242Crossref PubMed Scopus (582) Google Scholar), and a PDGFRβ+ neuroblast-like population has been found to respond to ischemia in stroke models (Sato et al., 2016Sato H. Ishii Y. Yamamoto S. Azuma E. Takahashi Y. Hamashima T. Umezawa A. Mori H. Kuroda S. Endo S. Sasahara M. Stem Cells. 2016; 34: 685-698Crossref PubMed Scopus (22) Google Scholar). Whether such suggestive links are red herrings or indicative of underlying principles are questions for future investigation. The striking finding of cortical development via an additional and unexpected route certainly requires independent confirmation. Although the authors already put considerable work into attempts to support their conclusions from different angles, their extraordinary claim deserves to be challenged and placed into a broader context. As with most exciting research, a large number of subsequent and detailed questions arise. Can this developmental principle be confirmed in other species? How did this complex developmental mechanism evolve? A link to the development of the brain's vasculature, during which the subarachnoid space forms and pia mater structures are drawn deep into the brain, seems obvious, but what does this exactly mean? Additionally, how do these developing Satb2+ neurons transition into the parenchyma proper? Is this class of developmentally distinct interneurons also functionally distinct, and are they heterogeneous with respect to the relationship between origin and function? And, perhaps the biggest question: how is this back door for contributing to neuronal populations orchestrated with cortical development as we know it? As in the world of expensive watch connoisseurs, an increasing appreciation for complications seems warranted for studying brain development. Neurogenic Radial Glia-like Cells in Meninges Migrate and Differentiate into Functionally Integrated Neurons in the Neonatal CortexBifari et al.Cell Stem CellNovember 23, 2016In BriefCarmeliet and colleagues have identified a population of radial glia-like neural progenitor cells located in the meninges of postnatal mice. After birth, these cells migrate through the caudal ventricular zone and then differentiate into functional and integrated neurons of the posterior cortex. Full-Text PDF Open Archive
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