Journal of Neurocytology

, Volume 33, Issue 3, pp 309–319 | Cite as

Engraftment and differentiation of neocortical progenitor cells transplanted to the embryonic brain in utero

  • Barbara Carletti
  • Piercesare Grimaldi
  • Lorenzo Magrassi
  • Ferdinando Rossi


Transplantation of neural progenitors or stem cells is a most useful tool to investigate the relative contribution of cell-autonomous mechanisms and environmental cues in the regulation of cell specification and differentiation during CNS development. To assess the capability of neocortical progenitor cells to integrate into foreign brain regions, here we examined the fate of precursor cells isolated from the dorsal telencephalon of E12 ß-actin-EGFP transgenic mouse embryos after heterotopic/heterochronic transplantation to the E16 rat brain in utero. Our observations show that donor cells were able to penetrate, survive and produce mature cell types into wide regions of the host CNS. Namely, EGFP-positive cells acquired site-specific neuronal identities in many telencephalic regions, including neocortex, hippocampus, olfactory bulb and corpus striatum. In contrast, incorporation into more caudal sites was much less efficient. A fraction of donor cells formed large aggregates that remained segregated from the host milieu. Such aggregates contained mature neurons and glia, including some EGFP-negative elements of host origin, and developed the complex organization of the mature nervous tissue. On the other hand, transplanted cells that engrafted in the parenchyma of extratelencephalic regions predominantly generated glial types. The few neurons failed to acquire obvious site-specific phenotypic traits and did not integrate into the local host architecture. Altogether, our observations indicate that E12 neocortical progenitors are already committed towards regional identities and are unable to modify their phenotypic choices when exposed to heterotopic environmental conditions along different rostro-caudal domains of the embryonic CNS.


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  1. ALTMANN, C. R. & BRIVANLOU, A. H. (2001) Neural patterning in the vertebrate embryo. International Review of Cytology 203, 447–482.PubMedGoogle Scholar
  2. ALVARADO-MALLART, R. M. (1993) Fate and potentialities of the avian mesencephalic/metencephalic neuroepithelium. Journal of Neurobiology 24, 1341–1355.PubMedGoogle Scholar
  3. ALVARADO-MALLART, R. M. & SOTELO, C. (1982) Differentiation of cerebellar anlage heterotopically transplanted to adult rat brain: A light and electron microscopic study. Journal of Comparative Neurology 212, 247–267.PubMedGoogle Scholar
  4. ANDERSON, D. J. (2001) Stem cells and pattern formation in the nervous system: The possible versus the actual. Neuron 30,19–35.PubMedGoogle Scholar
  5. BARBE, M. F. & LEVITT, P. (1991) The early commitment of fetal neurons in the limbic cortex. Journal of Neuroscience 11, 519–533.PubMedGoogle Scholar
  6. BERTRAND, N., CASTRO, D. S. & GUILLEMOT, F. (2002) Proneural genes and the specification of neural cell types. Nature Reviews Neuroscience 3, 517–530.PubMedGoogle Scholar
  7. BR ¨ USTLE, O., MASKOS, U. & MCKAY, R. D. G. (1995) Host-guided migration allows targeted introduction of neurons into the embryonic brain. Neuron 15, 1275–1285.PubMedGoogle Scholar
  8. CAMPBELL, K., OLSSON, M. & BJ ¨ ORKLUND, A. (1995) Regional incorporation and site-specific differentiation of striatal precursors transplanted to the embryonic fore-brain ventricle. Neuron 15, 1259–1273.PubMedGoogle Scholar
  9. CARLETTI, B., GRIMALDI, P., MAGRASSI, L. & ROSSI, F. (2002) Specification of cerebellar progenitors following heterotopic/heterochronic transplantation to the embryonic CNS in vivo and in vitro. Journal of Neuroscience 22, 7132–7146.PubMedGoogle Scholar
  10. CARLETTI, B., GRIMALDI, P., MAGRASSI, L. & ROSSI, F. (2003) Specification of cortical progenitors after.318 transplantation in the embryonic hindbrain. VI World IBRO Congress, abstract n. 1029.Google Scholar
  11. CATTANEO, E., MAGRASSI, L., BUTTI, G., SANTI, L., GIAVAZZI, A. & PEZZOTTA, S. (1994) A short term analysis of the behaviour of conditionally immortalized neuronal progenitors and primary neuroepithelial cells implanted into the fetal rat brain. Brain Research: Developmental Brain Research 83, 197–208.Google Scholar
  12. CELIO, M. R. (1990) Calbindin D-28k and parvalbumin in the rat nervous system. Neuroscience 2, 375–475.Google Scholar
  13. DESAI, A. R. & MCCONNELL, S. K. (2000) Progressive restriction in fate potential by neural progenitors during cerebral cortical development. Development 127, 2863–2872.PubMedGoogle Scholar
  14. FISHELL, G. (1995) Striatal precursors adopt cortical identities in response to local cues. Development 121, 803–812.PubMedGoogle Scholar
  15. FRANTZ, G. D. & MCCONNELL, S. K. (1996) Restriction of late cerebral cortical progenitors to an upper layer fate. Neuron 17,55–61.PubMedGoogle Scholar
  16. G ¨ OTZ, M., WIZENMANN, A., REINHARDT, S., LUMSDEN, A. & PRICE, J. (1996) Selective adhesion of cells from different telencephalic regions. Neuron 16, 551–564.PubMedGoogle Scholar
  17. JACOBOWITZ, D. M. & WINSHY, L. (1991) Immunocyto-chemical localization of calretinin in the forebrain of the rat. Journal of Comparative Neurology 304, 198–218.PubMedGoogle Scholar
  18. JANKOVSKI, A., ROSSI, F. & SOTELO, C. (1996) Neuronal precursors in the postnatal mouse cerebellum are fully committed cells: Evidence from heterochronic transplantation. European Journal of Neuroscience 8, 2308–2320.PubMedGoogle Scholar
  19. LIM, D. A., FISHELL, G. J. & ALVAREZ-BUYLLA, A. (1997) Postnatal mouse subventricular zone neuronal precursors can migrate and differentiate within multiple levels of the developing neuraxis. Proceedings of the National Academy of Science U.S.A. 26, 14832–14836.Google Scholar
  20. LUMSDEN, A., CLARKE, J. D. W., KEYNES, R. & FRASER, S. (1994) Early phenotypic choices by neuronal precursors, revealed by clonal analysis of the embryonic chick hindbrain. Development 120, 1581–1589.PubMedGoogle Scholar
  21. MAGRASSI, L., EHRLICH, M. E., BUTTI, G., PEZZOTTA, S., GOVONI, S. & CATTANEO, E. (1998) Basal ganglia precursors found in aggregates following embryonic transplantation adopt a striatal phenotype in heterotopic locations. Development 125, 2847–2855.PubMedGoogle Scholar
  22. McCARTHY, M., TURNBULL, D. H., WALSH, C. A. & FISHELL, G. (2001) Telencephalic neural progenitors appear to be restricted to regional and glial fates before the onset of neurogenesis. Journal of Neuroscience 21, 6772–6781.PubMedGoogle Scholar
  23. MORRISON, S. J. (2001) Neuronal differentiation: Proneural genes inhibit gliogenesis. Current Biology 11, R349–R351.PubMedGoogle Scholar
  24. MURRAY, K., CALAORA, V., ROTTKAMP, C., GUICHERIT, O. & DUBOIS-DALCQ, M. (2002) Sonic Hedgehog is a potent inducer of rat oligoden-drocyte development from cortical precursors in Vitro. Molecular and Cellular Neuroscience 19, 320–332.PubMedGoogle Scholar
  25. NA, E., McCARTHY, M., NEYT, C., LAI, E. & FISHELL, G. (1998) Telencephalic progenitors maintain anteroposterior identities cell autonomously. Current Biology 8, 987–990.PubMedGoogle Scholar
  26. NAKASHIMA, K., TAKIZAWA, T., OCHIAI, W., YANAGISAWA, H., NAKAFUKU, M., MIYAZONO, K., KISHIMOTO, T., KAGEYAMA, R. & TAGA, T. (2001) BMP2-mediated alteration in the developmental pathway of fetal mouse brain cells from neurogenesis to astrocytogenesis. Proceedings of the National Academy of Science U.S.A. 98, 5869–5875.Google Scholar
  27. NERY, S., WICHTERLE, H. & FISHELL, G. (2001) Sonic hedgehog contributes to oligodendrocyte specification in the mammalian forebrain. Development 128, 527–540.PubMedGoogle Scholar
  28. NIETO, M., SHUURMANS, C., BRITZ, O. & GUILLEMOT, F. (2001) Neural bHLH genes control the neuronal versus glial fate decision in cortical progenitors. Neuron 29, 401–413.PubMedGoogle Scholar
  29. OKABE, M., IKAWA, M., KOMINAMI, K., NAKANISHI, T. & NISHIMUNE, Y. (1997) "Green mice'' as a source of ubiquitous green cells. FEBS Letters 407, 313–319.PubMedGoogle Scholar
  30. OLSSON, M., CAMPBELL, K. & TURNBULL, D. H. (1997) Specification of mouse telencephalic and mid-hindbrain progenitors following heterotopic ultrasound-guided embryonic transplantation. Neuron 19, 761–772.PubMedGoogle Scholar
  31. OLSSON, M., BJERREGAARD, K., WINKLER, C., GATES, M., BJÖRKLUND, A. & CAMPBELL, K. (1998) Incorporation of mouse neural progenitors transplanted in the rat embryonic forebrain is developmentally regulated and dependent on regional adhesive properties. European Journal of Neuroscience 10,71–85.PubMedGoogle Scholar
  32. OUIMET, C. C., MILLER, P. E., HEMMINGS, H. C. JR., WALAAS, S. I. & GREENGARD, P. (1984) DARPP-32, a dopamine-and adenosine 3':5'-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. III. Immunocytochemical localization. Journal of Neuroscience 4, 111–124.PubMedGoogle Scholar
  33. PAXINOS, G. & WATSON, C. (1982) The Rat Brain in Stereo-taxic Coordinates. New York: Academic Press.Google Scholar
  34. QIAN, X., SHEN, Q., HE, W., CAPELA, A., DAVIS, A. A. & TEMPLE, S. (2000) Timing of CNS cell generation: A programmed sequence of neuron and glial cell production from isolated murine cortical stem cells. Neuron 28, 69–80.PubMedGoogle Scholar
  35. ROSSI, F. & CATTANEO, E. (2002) Neural stem cell therapy for neurological diseases: Dreams and reality. Nature Reviews Neuroscience 3, 401–409.PubMedGoogle Scholar
  36. ROSSI, F., BORSELLO, T. & STRATA, P. (1992) Embryonic Purkinje cells grafted on the surface of the cerebellar cortex integrate in the adult unlesioned cerebellum. European Journal of Neuroscience 4, 589–593.PubMedGoogle Scholar
  37. TAKAHASHI, M., PALMER, T., TAKAHASHI, J. & GAGE, F.H.(1998) Widespread integration and survival of adult-derived neural progenitor cells in the developing optic retina. Molecular and Cellular Neuroscience 12, 340–348.PubMedGoogle Scholar
  38. TEMPLE, S. (2001) The development of neural stem cells. Nature 414,112–117.PubMedGoogle Scholar
  39. VICARIO-ABEJON, C., CUNNINGHAM, M. G. & MC KAY R. D. G. (1995) Cerebellar precursors transplanted to the neonate dentate gyrus express features characteristic of hippocampal neurons. Journal of Neuroscience 15, 6351–6363.PubMedGoogle Scholar
  40. WASSEF, M., SOTELO, C., THOMASSET, M., GRANHOLM, A. C., LECLERC, N., RAFRAFI, J. & HAWKES, R. (1990) Expression of compartmentation.Fate of neocortical progenitors transplanted to the embryonic CNS 319 antigen zebrin I in cerebellar transplants. Journal of Comparative Neurology 294, 223–234.PubMedGoogle Scholar
  41. WILLIAMS, B. P. & PRICE, J. (1995) Evidence for multiple precursor cell types in the embryonic rat cerebral cortex. Neuron 14,1181–1188.PubMedGoogle Scholar
  42. YANAGISAWA, H., TAKIZAWA, T., OCHIAI, W., UEMURA, A., NAKASHIMA, K. & TAGA, T. (2001) Fate alteration of neuroepithelial cells from neurogenesis to astrocytogenesis by bone morphogenetic proteins. Neuroscience Research 41, 391–396.PubMedGoogle Scholar
  43. YANG, H., MUJTABA, T., VENKATRAMAN, G., WU, Y. Y., RAO, M. S. & LUSKIN, M. B. (2000) Region-specific differentiation of neural tube-derived neuronal restricted progenitor cells after heterotopic transplantation. Proceedings of the National Academy of Science U.S.A. 97, 13366–13371.Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Barbara Carletti
    • 1
  • Piercesare Grimaldi
    • 1
  • Lorenzo Magrassi
    • 2
  • Ferdinando Rossi
    • 2
  1. 1.Italy
  2. 2.Neurosurgery, Department of Surgery, IRCCS Policlinico S. Matteo, University of PaviaItaly

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