Central Nervous System; Neurobiology; Neurology; Apoptosis; Cell Proliferation
The long standing objective of research in this laboratory is to understand the cellular events and molecular mechanisms that govern development of the mammalian central nervous system. One line of investigation focuses on the fundamental issue of the regulation of cell proliferation and death (apoptosis) that determine the number of neurons allocated to the building of the cerebral cortex. The other series of studies concern molecular mechanisms involved in neuronal migration including cell-cell recognition, neuron glia-interaction and nuclear translocation.
Specialized Terms: Central nervous system development
Extensive Research Description
Research in this laboratory is focused on developmental neurobiology, more specifically on the mechanism of neuronal proliferation, migration, programmed cell death, axonal guidance, and patterns of synaptic connectivity and their plasticity during development of the central nervous system. One line of investigation focuses on the interaction between neuronal and glial cells during neuronal migration, the effects of various epigenetic factors on the development of structural, molecular and functional cell phenotypes, and their segregation into topographic maps.
Other research concerns the differentiation, synaptogenesis, and emergence of transmitters and their receptors in laminated structures (cerebellum, hippocampus, neocortex). Special emphasis has been on normal and experimentally altered development of the visual system following selective destruction of visual centers and/or pathways in developing primates. A battery of the most advanced methods are used with the hope of gaining insight into epigenetic sequences and the cellular and molecular mechanisms that regulate the development and evolution of the primate brain.The cerebral cortex provides the biological substrate for human cognitive capacity and is, arguably, the part of the brain that distinguishes us from other species. Therefore, understanding the evolution and development of this complex structure is central to our understanding of human intelligence, creativity and disorders of the highest cognitive functions. However, in our enthusiasm for universality of biological principles and a conservation of the genomic sequence, we sometimes forget that the heterogeneity among species is higher than expected from their genomic similarity. Even a small difference in the timing, sequence and level of gene expression may influence the phenotype in a major way. It seems obvious that one cannot understand specific human characteristics by looking only at a mouse model that does not possess these traits or have traits that have been lost.
We have new evidence that the species-specific size and characteristics of the cerebral neocortex are already detectable in the embryonic human forebrain before the onset of cortico-neurogenesis, but these early stages are not understood. Thirty-five years ago, the Boulder Committee recommended a blueprint and nomenclature for the development of the mammalian central nervous system, based on the model proposed by the applicant of this proposed grant. This model has been reproduced directly or in a modified form, in virtually every textbook of neuroembryology and the neurosciences, in general. However, the introduction of advanced methods and new concepts in developmental biology now necessitates an update of this basic schema.
The primary objective of the proposed research is to enhance our understanding of the molecular and cellular mechanisms underlying neuronal production, migration and positioning during early development of the cerebral cortex directly in humans. We propose to focus on the initial specification and cascade processes that establish the morphological and functional diversity of neurogenesis in the embryonic human telencephalon. We have recently obtained novel and unexpected evidence that the embryonic human telencephalic primordium, before the onset of local corticogenesis, contains a hitherto unrecognized transient population of neuronal cells. These "predecessor" cortical stem cells (new word!), are situated above the proliferative ventricular zone of the human telencephalon at the 4th week of gestation. We propose a radical idea that these neuronal stem cells are not homogeneous, but rather are already different amongst themselves. Furthermore, we speculate that these cells might initiate the cascade of developmental events leading to the formation of the cerebral cortex, which commences in human only about two weeks later. I am proposing that we try not only to characterize these new types of neural stem cells, but also to isolate and immortalize them with the most advanced methods.
Composite analyses of the gene expression patterns that we are going to perform will allow us to characterize the molecularly distinct progenitor domains in the forebrain primordium and to elucidate the genetic interactions underlying the early regionalization of the telencephalon directly in humans. We have unpublished evidence, which if elaborated, could alter one of the main concepts in the field of developmental neurobiology; namely, that the first neurons in the primordium of the human cerebral cortex (preplate zone) are generated outside of the developing cortex. To confirm these results, we are going to first perform modern cell-tracing experiments in slice culture preparations as well as immunohistochemical analysis to uncover the pattern of migration, connectivity and the role(s) of the pioneer neurons in the human telencephalon.
As a second step, dividing cells situated on the surface of the ex vivo human telencephalic vesicle obtained by legal abortion will be transiently transfected with a plasmid expressing fluorescent marker (GFP) under the control of the retroviral promoter. We will make shallow injections under the pial surface and after a brief recovery period, cells will be dissociated, single GFP expressing cells isolated, expanded with appropriate growth factors and then cryopreserved as cell aggregates. To produce stable clonal cell lines, cells will be infected with a retroviral vector expressing the v-myc fusion protein, propagated and characterized.
The project is designed to combine the expertise and unique experience in human brain development in my group at Yale, USA (including A. Ayoub and K. Hashimoto-Torii), C. Blakemore’s group at Oxford, UK (including I. Bystron and S. Lindsay) and V. Otellin’s group (Institute of Experimental Medicine, St. Petersburg, Russia). My laboratory has applied several new approaches in human brain tissue that involve a combination of organotypic culture and viral transduction to study the molecular mechanisms of cortical development (2); the Oxford group will provide expertise in the characterization of human neuronal cell lines (e.g. Bystron at al, 2005) and in vivo transplantation assays, and the St. Petersburg group has access to fresh embryonic brain tissue from legally performed interruption of pregnancies.
The emphasis on the early aspects of neuronal production, migration and positioning in human brain development will provide new insight into molecular evolution as well as in the pathogenesis of neuro-psychiatric disorders which affect millions of people of all ages which severely impacts the national economy. This information can only be obtained by studying early human forebrain neural stem cells.
Gap junctions/hemichannels modulate interkinetic nuclear migration in the forebrain precursors
Liu X, Hashimoto-Torii K, Torii M, Ding C, Rakic P. (2010) Gap junctions/hemichannels modulate interkinetic nuclear migration in the forebrain precursors J Neurosci. 30: 4197-209
Evolution of the neocortex: Perspective from developmental biology
Rakic, P. (2009) Evolution of the neocortex: Perspective from developmental biology. Nature Review Neurosci. 10, 724-735.
Integration of neuronal clones in the radial cortical columns by EphA/ephrin-A signaling.
Torii, M, Hashimoto-Torii, K, Levitt, P, and Rakic, P. (2009) Integration of neuronal clones in the radial cortical columns by EphA/ephrin-A signaling. Nature, 461: 524-528
Selective reduction of neuron number and volume of the mediodorsal nucleus of the thalamus in macaques following irradiation at early gestational ages.
Selemon LD, Begovic A, Rakic P. J Comp Neurol. 2009 Aug 1;515(4):454-64. PMID: 19459221 [PubMed - in process]
Exocyst is involved in polarized cell migration and cerebral cortical development.
Letinic K, Sebastian R, Toomre D, Rakic P. Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11342-7. Epub 2009 Jun 19. PMID: 19549839 [PubMed - indexed for MEDLINE]
Decision by division: making cortical maps.
Rakic P, Ayoub AE, Breunig JJ, Dominguez MH. Trends Neurosci. 2009 May;32(5):291-301. Epub 2009 Apr 18. Review. PMID: 19380167 [PubMed - indexed for MEDLINE]
Full List of PubMed Publications
- Benoit J, Ayoub A, Rakic P: Epigenetic stability in the adult mouse cortex under conditions of pharmacologically induced histone acetylation. Brain Struct Funct. 2016 Nov; 2015 Nov 2. PMID: 26526554
- Duque A, Krsnik Z, Kostović I, Rakic P: Secondary expansion of the transient subplate zone in the developing cerebrum of human and nonhuman primates. Proc Natl Acad Sci U S A. 2016 Aug 30; 2016 Aug 8. PMID: 27503885
- Son AI, Hashimoto-Torii K, Rakic P, Levitt P, Torii M: EphA4 has distinct functionality from EphA7 in the corticothalamic system during mouse brain development. J Comp Neurol. 2016 Jul 1; 2015 Dec 3. PMID: 26587807
- Rash BG, Ackman JB, Rakic P: Bidirectional radial Ca(2+) activity regulates neurogenesis and migration during early cortical column formation. Sci Adv. 2016 Feb 26; 2016 Feb 26. PMID: 26933693
- Morozov YM, Sun YY, Kuan CY, Rakic P: Alteration of SLP2-like immunolabeling in mitochondria signifies early cellular damage in developing and adult mouse brain. Eur J Neurosci. 2016 Jan; 2015 Dec 23. PMID: 26547131
- Benoit J, Ayoub AE, Rakic P: Transcriptomics of critical period of visual cortical plasticity in mice. Proc Natl Acad Sci U S A. 2015 Jun 30; 2015 Jun 15. PMID: 26080443
- Ayoub AE, Rakic P: Neuronal misplacement in schizophrenia. Biol Psychiatry. 2015 Jun 1. PMID: 25959564
- Benoit JD, Rakic P, Frick KM: Prenatal stress induces spatial memory deficits and epigenetic changes in the hippocampus indicative of heterochromatin formation and reduced gene expression. Behav Brain Res. 2015 Mar 15; 2014 Dec 8. PMID: 25496779
- Reilly SK, Yin J, Ayoub AE, Emera D, Leng J, Cotney J, Sarro R, Rakic P, Noonan JP: Evolutionary genomics. Evolutionary changes in promoter and enhancer activity during human corticogenesis. Science. 2015 Mar 6. PMID: 25745175
- Koch M, Varela L, Kim JG, Kim JD, Hernández-Nuño F, Simonds SE, Castorena CM, Vianna CR, Elmquist JK, Morozov YM, Rakic P, Bechmann I, Cowley MA, Szigeti-Buck K, Dietrich MO, Gao XB, Diano S, Horvath TL: Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature. 2015 Mar 5; 2015 Feb 18. PMID: 25707796
- Radonjić NV, Ayoub AE, Memi F, Yu X, Maroof A, Jakovcevski I, Anderson SA, Rakic P, Zecevic N: Diversity of cortical interneurons in primates: the role of the dorsal proliferative niche. Cell Rep. 2014 Dec 24; 2014 Dec 11. PMID: 25497090
- El Fatimy R, Miozzo F, Le Mouël A, Abane R, Schwendimann L, Sabéran-Djoneidi D, de Thonel A, Massaoudi I, Paslaru L, Hashimoto-Torii K, Christians E, Rakic P, Gressens P, Mezger V: Heat shock factor 2 is a stress-responsive mediator of neuronal migration defects in models of fetal alcohol syndrome. EMBO Mol Med. 2014 Jul 15; 2014 Jul 15. PMID: 25027850
- Sun YY, Morozov YM, Yang D, Li Y, Dunn RS, Rakic P, Chan PH, Abe K, Lindquist DM, Kuan CY: Synergy of combined tPA-edaravone therapy in experimental thrombotic stroke. PLoS One. 2014 Jun 9; 2014 Jun 9. PMID: 24911517
- Hashimoto-Torii K, Torii M, Fujimoto M, Nakai A, El Fatimy R, Mezger V, Ju MJ, Ishii S, Chao SH, Brennand KJ, Gage FH, Rakic P: Roles of heat shock factor 1 in neuronal response to fetal environmental risks and its relevance to brain disorders. Neuron. 2014 May 7; 2014 Apr 10. PMID: 24726381
- Rash BG, Rakic P: Neuroscience. Genetic resolutions of brain convolutions. Science. 2014 Feb 14. PMID: 24531964
- Dominguez MH, Ayoub AE, Rakic P: POU-III transcription factors (Brn1, Brn2, and Oct6) influence neurogenesis, molecular identity, and migratory destination of upper-layer cells of the cerebral cortex. Cereb Cortex. 2013 Nov; 2012 Aug 14. PMID: 22892427
- Morozov YM, Dominguez MH, Varela L, Shanabrough M, Koch M, Horvath TL, Rakic P: Antibodies to cannabinoid type 1 receptor co-react with stomatin-like protein 2 in mouse brain mitochondria. Eur J Neurosci. 2013 Aug; 2013 Apr 26. PMID: 23617247
- Cotney J, Leng J, Yin J, Reilly SK, DeMare LE, Emera D, Ayoub AE, Rakic P, Noonan JP: The evolution of lineage-specific regulatory activities in the human embryonic limb. Cell. 2013 Jul 3. PMID: 23827682
- Torii M, Hackett TA, Rakic P, Levitt P, Polley DB: EphA signaling impacts development of topographic connectivity in auditory corticofugal systems. Cereb Cortex. 2013 Apr; 2012 Apr 5. PMID: 22490549
- Selemon LD, Ceritoglu C, Ratnanather JT, Wang L, Harms MP, Aldridge K, Begović A, Csernansky JG, Miller MI, Rakic P: Distinct abnormalities of the primate prefrontal cortex caused by ionizing radiation in early or midgestation. J Comp Neurol. 2013 Apr 1. PMID: 22911497
- Torii M, Rakic P, Levitt P: Role of EphA/ephrin--a signaling in the development of topographic maps in mouse corticothalamic projections. J Comp Neurol. 2013 Feb 15. PMID: 22821544
- Liu X, Sun L, Torii M, Rakic P: Connexin 43 controls the multipolar phase of neuronal migration to the cerebral cortex. Proc Natl Acad Sci U S A. 2012 May 22; 2012 May 7. PMID: 22566616
- Kwan KY, Lam MM, Johnson MB, Dube U, Shim S, Rašin MR, Sousa AM, Fertuzinhos S, Chen JG, Arellano JI, Chan DW, Pletikos M, Vasung L, Rowitch DH, Huang EJ, Schwartz ML, Willemsen R, Oostra BA, Rakic P, Heffer M, Kostović I, Judaš M, Sestan N: Species-dependent posttranscriptional regulation of NOS1 by FMRP in the developing cerebral cortex. Cell. 2012 May 11. PMID: 22579290
- Arellano JI, Guadiana SM, Breunig JJ, Rakic P, Sarkisian MR: Development and distribution of neuronal cilia in mouse neocortex. J Comp Neurol. 2012 Mar 1. PMID: 22020803
- Duque A, Rakic P: Different effects of bromodeoxyuridine and [3H]thymidine incorporation into DNA on cell proliferation, position, and fate. J Neurosci. 2011 Oct 19. PMID: 22016554
- Ayoub AE, Oh S, Xie Y, Leng J, Cotney J, Dominguez MH, Noonan JP, Rakic P: Transcriptional programs in transient embryonic zones of the cerebral cortex defined by high-resolution mRNA sequencing. Proc Natl Acad Sci U S A. 2011 Sep 6; 2011 Aug 22. PMID: 21873192
- Breunig JJ, Haydar TF, Rakic P: Neural stem cells: historical perspective and future prospects. Neuron. 2011 May 26. PMID: 21609820
- Breunig JJ, Rakic P: Coordinating migratory neuron polarization by numb-ing communication. Dev Cell. 2011 May 17. PMID: 21571215
- Hashimoto-Torii K, Kawasawa YI, Kuhn A, Rakic P: Combined transcriptome analysis of fetal human and mouse cerebral cortex exposed to alcohol. Proc Natl Acad Sci U S A. 2011 Mar 8; 2011 Feb 22. PMID: 21368140
- Imamura F, Ayoub AE, Rakic P, Greer CA: Timing of neurogenesis is a determinant of olfactory circuitry. Nat Neurosci. 2011 Mar; 2011 Feb 6. PMID: 21297629
- Breunig JJ, Rakic P: Profiling identifies precursor suspects: notch family again! Cell Stem Cell. 2010 May 7. PMID: 20452310
- Liu X, Hashimoto-Torii K, Torii M, Ding C, Rakic P: Gap junctions/hemichannels modulate interkinetic nuclear migration in the forebrain precursors. J Neurosci. 2010 Mar 24. PMID: 20335455
- Rakic P: Evolution of the neocortex: a perspective from developmental biology. Nat Rev Neurosci. 2009 Oct. PMID: 19763105
- Torii M, Hashimoto-Torii K, Levitt P, Rakic P: Integration of neuronal clones in the radial cortical columns by EphA and ephrin-A signalling. Nature. 2009 Sep 24; 2009 Sep 16. PMID: 19759535
- Selemon LD, Begović A, Rakic P: Selective reduction of neuron number and volume of the mediodorsal nucleus of the thalamus in macaques following irradiation at early gestational ages. J Comp Neurol. 2009 Aug 1. PMID: 19459221
- Letinic K, Sebastian R, Toomre D, Rakic P: Exocyst is involved in polarized cell migration and cerebral cortical development. Proc Natl Acad Sci U S A. 2009 Jul 7; 2009 Jun 19. PMID: 19549839
- Morozov YM, Torii M, Rakic P: Origin, early commitment, migratory routes, and destination of cannabinoid type 1 receptor-containing interneurons. Cereb Cortex. 2009 Jul; 2009 Apr 3. PMID: 19346272
- Rakic P, Ayoub AE, Breunig JJ, Dominguez MH: Decision by division: making cortical maps. Trends Neurosci. 2009 May; 2009 Apr 18. PMID: 19380167
- Hashimoto-Torii K, Torii M, Sarkisian MR, Bartley CM, Shen J, Radtke F, Gridley T, Sestan N, Rakic P: Interaction between Reelin and Notch signaling regulates neuronal migration in the cerebral cortex. Neuron. 2008 Oct 23. PMID: 18957219
- Rakic P: Confusing cortical columns. Proc Natl Acad Sci U S A. 2008 Aug 26; 2008 Aug 20. PMID: 18715998
- Liu X, Hashimoto-Torii K, Torii M, Haydar TF, Rakic P: The role of ATP signaling in the migration of intermediate neuronal progenitors to the neocortical subventricular zone. Proc Natl Acad Sci U S A. 2008 Aug 19; 2008 Aug 8. PMID: 18689674
- Dominguez MH, Rakic P: Neuroanatomy of the FGF system. J Comp Neurol. 2008 Jul 10. PMID: 18459136
- Town T, Breunig JJ, Sarkisian MR, Spilianakis C, Ayoub AE, Liu X, Ferrandino AF, Gallagher AR, Li MO, Rakic P, Flavell RA: The stumpy gene is required for mammalian ciliogenesis. Proc Natl Acad Sci U S A. 2008 Feb 26; 2008 Feb 19. PMID: 18287022
- Sarkisian MR, Bartley CM, Rakic P: Trouble making the first move: interpreting arrested neuronal migration in the cerebral cortex. Trends Neurosci. 2008 Feb; 2008 Jan 16. PMID: 18201775
- Breunig JJ, Silbereis J, Vaccarino FM, Sestan N, Rakic P: Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus. Proc Natl Acad Sci U S A. 2007 Dec 18; 2007 Dec 11. PMID: 18077357
- Breunig JJ, Arellano JI, Macklis JD, Rakic P: Everything that glitters isn't gold: a critical review of postnatal neural precursor analyses. Cell Stem Cell. 2007 Dec 13. PMID: 18371403
- Rakic P: The radial edifice of cortical architecture: from neuronal silhouettes to genetic engineering. Brain Res Rev. 2007 Oct; 2007 Mar 31. PMID: 17467805
- Rakic P: Forward to the special issue on the prefrontal cortex and working memory: in memory of Patricia S. Goldman-Rakic. Cereb Cortex. 2007 Sep. PMID: 17725992
- Rasin MR, Gazula VR, Breunig JJ, Kwan KY, Johnson MB, Liu-Chen S, Li HS, Jan LY, Jan YN, Rakic P, Sestan N: Numb and Numbl are required for maintenance of cadherin-based adhesion and polarity of neural progenitors. Nat Neurosci. 2007 Jul; 2007 Jun 24. PMID: 17589506
- Rakic P, Hashimoto-Torii K, Sarkisian MR: Genetic determinants of neuronal migration in the cerebral cortex. Novartis Found Symp. 2007. PMID: 18494251
- Sarkisian MR, Bartley CM, Chi H, Nakamura F, Hashimoto-Torii K, Torii M, Flavell RA, Rakic P: MEKK4 signaling regulates filamin expression and neuronal migration. Neuron. 2006 Dec 7. PMID: 17145501
- Janusonis S, Anderson GM, Shifrovich I, Rakic P: Ontogeny of brain and blood serotonin levels in 5-HT receptor knockout mice: potential relevance to the neurobiology of autism. J Neurochem. 2006 Nov; 2006 Sep 18. PMID: 16981893
- Paspalas CD, Rakic P, Goldman-Rakic PS: Internalization of D2 dopamine receptors is clathrin-dependent and select to dendro-axonic appositions in primate prefrontal cortex. Eur J Neurosci. 2006 Sep. PMID: 16987224
- Ang ES Jr, Gluncic V, Duque A, Schafer ME, Rakic P: Prenatal exposure to ultrasound waves impacts neuronal migration in mice. Proc Natl Acad Sci U S A. 2006 Aug 22; 2006 Aug 10. PMID: 16901978
- Rakic P: Neuroscience. No more cortical neurons for you. Science. 2006 Aug 18. PMID: 16917050
- Rakic P: A century of progress in corticoneurogenesis: from silver impregnation to genetic engineering. Cereb Cortex. 2006 Jul. PMID: 16766705
- Morozov YM, Ayoub AE, Rakic P: Translocation of synaptically connected interneurons across the dentate gyrus of the early postnatal rat hippocampus. J Neurosci. 2006 May 10. PMID: 16687493
- Rakic P: Vive la difference! Neuron. 2005 Aug 4. PMID: 16055054
- Chi H, Sarkisian MR, Rakic P, Flavell RA: Loss of mitogen-activated protein kinase kinase kinase 4 (MEKK4) results in enhanced apoptosis and defective neural tube development. Proc Natl Acad Sci U S A. 2005 Mar 8; 2005 Feb 24. PMID: 15731347
- Selemon LD, Wang L, Nebel MB, Csernansky JG, Goldman-Rakic PS, Rakic P: Direct and indirect effects of fetal irradiation on cortical gray and white matter volume in the macaque. Biol Psychiatry. 2005 Jan 1. PMID: 15607304
- Rakic P: Neuroscience. Genetic control of cortical convolutions. Science. 2004 Mar 26. PMID: 15044793
- Markakis EA, Palmer TD, Randolph-Moore L, Rakic P, Gage FH: Novel neuronal phenotypes from neural progenitor cells. J Neurosci. 2004 Mar 24. PMID: 15044527
- Janusonis S, Gluncic V, Rakic P: Early serotonergic projections to Cajal-Retzius cells: relevance for cortical development. J Neurosci. 2004 Feb 18. PMID: 14973240
- Hunot S, Vila M, Teismann P, Davis RJ, Hirsch EC, Przedborski S, Rakic P, Flavell RA: JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A. 2004 Jan 13; 2004 Jan 2. PMID: 14704277
- Li MO, Sarkisian MR, Mehal WZ, Rakic P, Flavell RA: Phosphatidylserine receptor is required for clearance of apoptotic cells. Science. 2003 Nov 28. PMID: 14645847
- Ang ES Jr, Haydar TF, Gluncic V, Rakic P: Four-dimensional migratory coordinates of GABAergic interneurons in the developing mouse cortex. J Neurosci. 2003 Jul 2. PMID: 12843285
- Rakic P: Elusive radial glial cells: historical and evolutionary perspective. Glia. 2003 Jul. PMID: 12761862
- Rakic P: Developmental and evolutionary adaptations of cortical radial glia. Cereb Cortex. 2003 Jun. PMID: 12764027
- Haydar TF, Ang E Jr, Rakic P: Mitotic spindle rotation and mode of cell division in the developing telencephalon. Proc Natl Acad Sci U S A. 2003 Mar 4; 2003 Feb 14. PMID: 12589023
- Gelowitz DL, Rakic P, Goldman-Rakic PS, Selemon LD: Craniofacial dysmorphogenesis in fetally irradiated nonhuman primates: implications for the neurodevelopmental hypothesis of schizophrenia. Biol Psychiatry. 2002 Oct 1. PMID: 12372662
- Letinic K, Zoncu R, Rakic P: Origin of GABAergic neurons in the human neocortex. Nature. 2002 Jun 6. PMID: 12050665
- Rakic P: Adult neurogenesis in mammals: an identity crisis. J Neurosci. 2002 Feb 1. PMID: 11826088
- Rakic P: Neurogenesis in adult primate neocortex: an evaluation of the evidence. Nat Rev Neurosci. 2002 Jan. PMID: 11823806
- Rakic P: Neurogenesis in adult primates. Prog Brain Res. 2002. PMID: 12432759
- Rakic P: Evolving concepts of cortical radial and areal specification. Prog Brain Res. 2002. PMID: 12143387