Spatiotemporal Distribution of PAX6 and MEIS2 Expression and Total Cell Numbers in the Ganglionic Eminence in the Early Developing Human ForebrainLarsen K.B.a, b · Lutterodt M.C.c, d · Laursen H.e · Græm N.e · Pakkenberg B.b · Møllgård K.f · Møller M.a
aDepartment of Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen, bResearch Laboratory for Stereology and Neuroscience, Bispebjerg Hospital, cLaboratory of Biology and Reproduction, Rigshospitalet, dDepartment of Gynecology and Obstetrics, Frederiksberg Hospital, eDepartment of Pathology, Rigshospitalet, and fDepartment of Cellular and Molecular Medicine, Developmental Biology Unit, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Article / Publication Details
The development of the human neocortex is a complex and highly regulated process involving a time-related expression of many transcription factors including the homeobox genes Pax6 and Meis2. During early development, Pax6 is expressed in nuclei of radial glia cells in the neocortical proliferative zones and controls the differentiation and neurogenetic fate of these cells in the dorsal telencephalon in rodents. Animal studies on the Meis2 gene have revealed expression in the developing telencephalon and Meis2 is known to regulate the expression of Pax6 in the eye and pancreas. Because of this functional relation between Pax6 and Meis2, we studied the spatial and temporal expression of PAX6, and MEIS2 using a developmental series of human fetal brains at 7–19 postconceptional weeks with emphasis on the forebrain to investigate whether the two genes are expressed in the same regions and zones in the same time window. We demonstrate by in situ hybridization and immunohistochemistry that the two homeobox genes are expressed during early fetal brain development in humans. PAX6 mRNA and protein were located in the proliferative zones of the neocortex and in single cells in the cortical preplate at 7 fetal weeks and in the developing cortical plate from 8 or 9 to 19 fetal weeks. The expression of PAX6 expanded into the ganglionic eminence just prior to the stage at which a stereological estimation showed an exponential rise in total cell number in this area. The MEIS2 gene was also present in the proliferative zones of the human fetal neocortex and a higher expression of MEIS2 than PAX6 was observed in these areas at 9 fetal weeks. Further, MEIS2 was expressed at a very high level in the developing ganglionic eminence and at a more moderate level in the cortical plate.
© 2010 S. Karger AG, Basel
- Agoston Z, Schulte D (2009): Meis2 competes with the Groucho co-repressor Tle4 for binding to Otx2 and specifies tectal fate without induction of a secondary midbrain-hindbrain boundary organizer. Development 136:3311–3322.
Altman PL, Dittmer DS (1962): Growth, including reproduction and morphological development. Washington, Federation of American Societies for Experimental Biology.
- Anderson SA, Eisenstat DD, Shi L, Rubenstein JL (1997): Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes. Science 278:474–476.
- Bayatti N, Moss JA, Sun L, Ambrose P, Ward JF, Lindsay S, Clowry GJ (2008a): A molecular neuroanatomical study of the developing human neocortex from 8 to 17 postconceptional weeks revealing the early differentiation of the subplate and subventricular zone. Cereb Cortex 18:1536–1548.
- Bayatti N, Sarma S, Shaw C, Eyre JA, Vouyiouklis DA, Lindsay S, Clowry GJ (2008b): Progressive loss of PAX6, TBR2, NEUROD and TBR1 mRNA gradients correlates with translocation of EMX2 to the cortical plate during human cortical development. Eur J Neurosci 28:1449–1456.
Bayer SA, Altman J (2006a): The Human Brain during the Second Trimester. New York, Taylor & Francis Group, vol 3.
Bayer SA, Altman J (2006b): The Human Brain during the Late First Trimester. New York, Taylor & Francis Group, vol 4.
- Biemar F, Devos N, Martial JA, Driever W, Peers B (2001): Cloning and expression of the TALE superclass homeobox Meis2 gene during zebrafish embryonic development. Mech Dev 109:427–431.
- Bumsted-O’Brien KM, Hendrickson A, Haverkamp S, Ashery-Padan R, Schulte D (2007): Expression of the homeodomain transcription factor Meis2 in the embryonic and postnatal retina. J Comp Neurol 505:58–72.
- Bürglin TR (1997): Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals. Nucleic Acids Res 25:4173–4180.
- Bystron I, Molnár Z, Otellin V, Blakemore C (2005): Tangential networks of precocious neurons and early axonal outgrowth in the embryonic human forebrain. J Neurosci 25:2781–2792.
- Bystron I, Rakic P, Molnár Z, Blakemore C (2006): The first neurons of the human cerebral cortex. Nat Neurosci 880–886.
- Bystron I, Blakemore C, Rakic P (2008): Development of the human cerebral cortex: Boulder Committee revisited. Nat Rev Neurosci 9:110–122.
- Cecconi F, Proetzel G, Alvarez-Bolado G, Jay D, Gruss P (1997): Expression of Meis2, a Knotted-related murine homeobox gene, indicates a role in the differentiation of the forebrain and the somitic mesoderm. Dev Dyn 210:184–190.
- Chi N, Epstein JA (2002): Getting your Pax straight: Pax proteins in development and disease. Trends Genet 18:41–47.
- Dorph-Petersen KA, Nyengaard JR, Gundersen HJ (2001): Tissue shrinkage and unbiased stereological estimation of particle number and size. J Microsc 204:232–246.
- Englund C, Fink A, Lau C, Pham D, Daza RA, Bulfone A, Kowalczyk T, Hevner R (2005): Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex. J Neurosci 25:247–251.
- Ferran JL, Sánchez-Arrones L, Sandoval JE, Puelles L (2007): A model of early molecular regionalization in the chicken embryonic pretectum. J Comp Neurol 505:379–403.
- Fertuzinhos S, Krsnik Z, Kawasawa YI, Rasin MR, Kwan KY, Chen JG, Judas M, Hayashi M, Sestan N (2009): Selective depletion of molecularly defined cortical interneurons in human holoprosencephaly with severe striatal hypoplasia. Cereb Cortex 19:2196–2207.
- Finlay BL, Darlington RB (1995): Linked regularities in the development and evolution of mammalian brains. Science 268:1578–1584.
- Ghanem N, Yu M, Poitras L, Rubenstein JL, Ekker M (2008): Characterization of a distinct subpopulation of striatal projection neurons expressing the Dlx genes in the basal ganglia through the activity of the I56ii enhancer. Dev Biol 322:415–424.
- Gotz M, Stoykova A, Gruss P (1998): Pax6 controls radial glia differentiation in the cerebral cortex. Neuron 21:1031–1044.
- Gundersen HJ (1986): Stereology of arbitrary particles. A review of unbiased number and size estimators and the presentation of some new ones, in memory of William R. Thompson. J Microsc 143:3–45.
- Gundersen HJ, Jensen EB, Kiêu K, Nielsen J (1999): The efficiency of systematic sampling in stereology – reconsidered. J Microsc 193:199–211.
- Heine P, Dohle E, Bumsted-O’Brien K, Engelkamp D, Schulte D (2008): Evidence for an evolutionary conserved role of homothorax/Meis1/2 during vertebrate retina development. Development 135:805–811.
- Heins N, Malatesta P, Cecconi F, Nakafuku M, Tucker KL, Hack MA, Chapouton P, Barde YA, Gotz M (2002): Glial cells generate neurons: the role of the transcription factor Pax6. Nat Neurosci 5:308–315.
- Howard BM, Zhicheng Mo, Filipovic R, Moore AR, Antic SD, Zecevic N (2008): Radial glia cells in the developing human brain. Neuroscientist 14:459–473.
- Huang H, Xue R, Zhang J, Ren T, Richards LJ, Yarowsky P, Miller MI, Mori S (2009): Anatomical characterization of human fetal brain development with diffusion tensor magnetic resonance imaging. J Neurosci 29:4263–4273.
- Kriegstein AR, Gotz M (2003): Radial glia diversity: a matter of cell fate. Glia 43:37–43.
- Lang D, Powell SK, Plummer RS, Young KP, Ruggeri BA (2007): PAX genes: roles in development, pathophysiology, and cancer. Biochem Pharmacol 73:1–14.
- Larsen KB, Lutterodt M, Rath MF, Møller M (2009): Expression of the homeobox genes PAX6, OTX2, and OTX1 in the early human fetal retina. Int J Dev Neurosci 27:485–492.
- Letinic K, Zoncu R, Rakic P (2002): Origin of GABAergic neurons in the human neocortex. Nature 417:645–649.
- Lindsay S, Sarma S, Martinez-de-la-Torre M, Kerwin J, Scott M, Luis Ferran J, Baldock R, Puelles L (2005): Anatomical and gene expression mapping of the ventral pallium in a three-dimensional model of developing human brain. Neuroscience 136:625–632.
- Lutterodt MC, Rosendahl M, Andersen CY, Skouby SO, Byskov AG (2009): Age determination enhanced by embryonic foot bud and foot plate measurements in relation to Carnegie stages, and the influence of maternal cigarette smoking. Hum Reprod 24:1825–1833.
- Lyngholm M, Høyer PE, Vorum H, Nielsen K, Ehlers N, Møllgård K (2008): Immunohistochemical markers for corneal stem cells in the early developing human eye. Exp Eye Res 87:115–121.
- Malatesta P, Hack MA, Hartfuss E, Kettenmann H, Klinkert W, Kirchhoff F, Gotz M (2003): Neuronal or glial progeny: regional differences in radial glia fate. Neuron 37:751–764.
- Malatesta P, Hartfuss E, Gotz M (2000): Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development 127:5253–5263.
- Miyata T, Kawaguchi A, Okano H, Ogawa M (2001): Asymmetric inheritance of radial glial fibers by cortical neurons. Neuron 31:727–741.
- Mo Z, Zecevic N (2008): Is Pax6 critical for neurogenesis in the human fetal brain? Cereb Cortex 18:1455–1465.
- Moskow JJ, Bullrich F, Huebner K, Daar IO, Buchberg AM (1995): Meis1, a PBX1-related homeobox gene involved in myeloid leukemia in BXH-2 mice. Mol Cell Biol 15:5434–5443.
- Nakamura T, Jenkins NA, Copeland NG (1996): Identification of a new family of Pbx-related homeobox genes. Oncogene 13:2235–2242.
- Noctor SC, Flint AC, Weissman TA, Dammerman RS, Kriegstein AR (2001): Neurons derived from radial glial cells establish radial units in neocortex. Nature 409:714–720.
- O’Leary DD, Nakagawa Y (2002): Patterning centers, regulatory genes and extrinsic mechanisms controlling arealization of the neocortex. Curr Opin Neurobiol 12:14–25.
- O’Rahilly R (1979): Early human development and the chief sources of information on staged human embryos. Eur J Obstet Gynecol Reprod Biol 9:273–280.
- Oulad-Abdelghani M, Chazaud C, Bouillet P, Sapin V, Chambon P, Dollé P (1997): Meis2, a novel mouse Pbx-related homeobox gene induced by retinoic acid during differentiation of P19 embryonal carcinoma cells. Dev Dyn 210:173–183.
- Pennartz S, Belvindrah R, Tomiuk S, Zimmer C, Hofmann K, Conradt M, Bosio A, Cremer H (2004): Purification of neuronal precursors from the adult mouse brain: comprehensive gene expression analysis provides new insights into the control of cell migration, differentiation, and homeostasis. Mol Cell Neurosci 25:692–706.
- Rados M, Judas M, Kostović I (2006): In vitro MRI of brain development. Eur J Radiol 57:187–198.
- Rath MF, Morin F, Shi Q, Klein DC, Møller M (2007): Ontogenetic expression of the Otx2 and Crx homeobox genes in the retina of the rat. Exp Eye Res 85:65–73.
- Samuelsen GB, Larsen KB, Bogdanovic N, Laursen H, Graem N, Larsen JF, Pakkenberg B (2003): The changing number of cells in the human fetal forebrain and its subdivisions: a stereological analysis. Cereb Cortex 115–122.
- Sander M, Neubüser A, Kalamaras J, Ee HC, Martin GR, German MS (1997): Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development. Genes Dev 11:1662–1673.
- Shim S, Kim Y, Shin J, Kim J, Park S (2007): Regulation of EphA8 gene expression by TALE homeobox transcription factors during development of the mesencephalon. Mol Cell Biol 27:1614–1630.
- Smith JE, Afonja O, Yee HT, Inghirami G, Takeshita K (1997a): Chromosomal mapping to 15q14 and expression analysis of the human MEIS2 homeobox gene. Mamm Genome 8:951–952.
- Smith JE Jr, Bollekens JA, Inghirami G, Takeshita K (1997b): Cloning and mapping of the MEIS1 gene, the human homolog of a murine leukemogenic gene. Genomics 43:99–103.
- Stagaard Janas M, Nowakowski RS, Møllgård K (1991): Glial cell differentiation in neuron-free and neuron-rich regions. II. Early appearance of S-100 protein positive astrocytes in human fetal hippocampus. Anat Embryol (Berl) 184:559–569.
- Stanescu D, Iseli HP, Schwerdtfeger K, Ittner LM, Remé CE, Hafezi F (2007): Continuous expression of the homeobox gene Pax6 in the ageing human retina. Eye 21:90–93.
- Stedman A, Lecaudey V, Havis E, Anselme I, Wassef M, Gilardi-Hebenstreit P, Schneider-Maunoury S (2009): A functional interaction between Irx and Meis patterns the anterior hindbrain and activates krox20 expression in rhombomere 3. Dev Biol 327:566–577.
- Sterio DC (1984): The unbiased estimation of number and sizes of arbitrary particles using the disector. J Microsc 134:127–136.
- Stoykova A, Gruss P (1994): Roles of Pax-genes in developing and adult brain as suggested by expression patterns. J Neurosci 14:1395–1412.
- Sugiyama S, Di Nardo AA, Aizawa S, Matsuo I, Volovitch M, Prochiantz A, Hensch TK (2008): Experience-dependent transfer of Otx2 homeoprotein into the visual cortex activates postnatal plasticity. Cell 134:508–520.
- Swift GH, Liu Y, Rose SD, Bischof LJ, Steelman S, Buchberg AM, Wright CV, MacDonald RJ (1998): An endocrine-exocrine switch in the activity of the pancreatic homeodomain protein PDX1 through formation of a trimeric complex with PBX1b and MRG1 (MEIS2). Mol Cell Biol 18:5109–5120.
- Takahashi K, Liu FC, Oishi T, Mori T, Higo N, Hayashi M, Hirokawa K, Takahashi H (2008): Expression of FOXP2 in the developing monkey forebrain: comparison with the expression of the genes FOXP1, PBX3, and MEIS2. J Comp Neurol 509:180–189.
- Tamamaki N, Fujimori KE, Takauji R (1997): Origin and route of tangentially migrating neurons in the developing neocortical intermediate zone. J Neurosci 17:8313–8323.
- Terzic J, Saraga-Babic M (1999): Expression pattern of PAX3 and PAX6 genes during human embryogenesis. Int J Dev Biol 43:501–508.
Theiler K (1972): The House Mouse. Berlin, Springer.
- Toresson H, Mata de Urquiza A, Fagerström C, Perlmann T, Campbell K (1999): Retinoids are produced by glia in the lateral ganglionic eminence and regulate striatal neuron differentiation. Development 126:1317–1326.
- Toresson H, Parmar M, Campbell K (2000): Expression of Meis and Pbx genes and their protein products in the developing telencephalon: implications for regional differentiation. Mech Dev 94:183–187.
- Treisman J, Harris E, Desplan C (1991): The paired box encodes a second DNA-binding domain in the paired homeo domain protein. Genes Dev 5:594–604.
- Ulfig N (2002): Ganglionic eminence of the human fetal brain – new vistas. Anat Rec 267:191–195.
- Walther C, Gruss P (1991): Pax-6, a murine paired box gene, is expressed in the developing CNS. Development 113:1435–1449.
- Waskiewicz AJ, Rikhof HA, Hernandez RE, Moens CB (2001): Zebrafish Meis functions to stabilize Pbx proteins and regulate hindbrain patterning. Development 128:4139–4151.
- Wassef MA, Chomette D, Pouilhe M, Stedman A, Havis E, Desmarquet-Trin Dinh C, Schneider-Maunoury S, Gilardi-Hebenstreit P, Charnay P, Ghislain J (2008): Rostral hindbrain patterning involves the direct activation of a Krox20 transcriptional enhancer by Hox/Pbx and Meis factors. Development 135:3369–3378.
- West MJ, Slomianka L, Gundersen HJ (1991): Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 231:482–497.
- Yun K, Potter S, Rubenstein JL (2001): Gsh2 and Pax6 play complementary roles in dorsoventral patterning of the mammalian telencephalon. Development 128:193–205.
- Zerucha T, Prince VE (2001): Cloning and developmental expression of a zebrafish meis2 homeobox gene. Mech Dev 102:247–250.
- Zhang X, Friedman A, Heaney S, Purcell P, Maas RL (2002a): Meis homeoproteins directly regulate Pax6 during vertebrate lens morphogenesis. Genes Dev 16:2097–2107.
- Zhang X, Rowan S, Yue Y, Heaney S, Pan Y, Brendolan A, Selleri L, Maas RL (2006): Pax6 is regulated by Meis and Pbx homeoproteins during pancreatic development. Dev Biol 300:748–757.
- Zhang YA, Okada A, Lew CH, McConnell SK (2002b): Regulated nuclear trafficking of the homeodomain protein otx1 in cortical neurons. Mol Cell Neurosci 19:430–446.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.