Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 319 (5861): 304-309

Copyright © 2008 by the American Association for the Advancement of Science

Lhx2 Selector Activity Specifies Cortical Identity and Suppresses Hippocampal Organizer Fate

Vishakha S. Mangale,1* Karla E. Hirokawa,2* Prasad R. V. Satyaki,1* Nandini Gokulchandran,1* Satyadeep Chikbire,1 Lakshmi Subramanian,1 Ashwin S. Shetty,1 Ben Martynoga,1 Jolly Paul,1 Mark V. Mai,3 Yuqing Li,4 Lisa A. Flanagan,5 Shubha Tole,1{dagger} Edwin S. Monuki2,5{dagger}

Abstract: The earliest step in creating the cerebral cortex is the specification of neuroepithelium to a cortical fate. Using mouse genetic mosaics and timed inactivations, we demonstrated that Lhx2 acts as a classic selector gene and essential intrinsic determinant of cortical identity. Lhx2 selector activity is restricted to an early critical period when stem cells comprise the cortical neuroepithelium, where it acts cell-autonomously to specify cortical identity and suppress alternative fates in a spatially dependent manner. Laterally, Lhx2 null cells adopt antihem identity, whereas medially they become cortical hem cells, which can induce and organize ectopic hippocampal fields. In addition to providing functional evidence for Lhx2 selector activity, these findings show that the cortical hem is a hippocampal organizer.

1 Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
2 Department of Developmental and Cell Biology, School of Biological Sciences, University of California Irvine, Irvine, CA 92697, USA.
3 Department of Biology, Swarthmore College, Swarthmore, PA 19081, USA.
4 Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
5 Department of Pathology and Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA 92697, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: emonuki{at} (E.S.M., cKO component); stole{at} (S.T., ESC chimeras)

Lhx2 Regulates the Development of the Forebrain Hem System.
A. Roy, M. Gonzalez-Gomez, A. Pierani, G. Meyer, and S. Tole (2014)
Cereb Cortex 24, 1361-1372
   Abstract »    Full Text »    PDF »
Zbtb20 Defines a Hippocampal Neuronal Identity Through Direct Repression of Genes That Control Projection Neuron Development in the Isocortex.
J. V. Nielsen, M. Thomassen, K. Mollgard, J. Noraberg, and N. A. Jensen (2014)
Cereb Cortex 24, 1216-1229
   Abstract »    Full Text »    PDF »
The LIM and POU homeobox genes ttx-3 and unc-86 act as terminal selectors in distinct cholinergic and serotonergic neuron types.
F. Zhang, A. Bhattacharya, J. C. Nelson, N. Abe, P. Gordon, C. Lloret-Fernandez, M. Maicas, N. Flames, R. S. Mann, D. A. Colon-Ramos, et al. (2014)
Development 141, 422-435
   Abstract »    Full Text »    PDF »
Lhx2 regulates a cortex-specific mechanism for barrel formation.
A. S. Shetty, G. Godbole, U. Maheshwari, H. Padmanabhan, R. Chaudhary, B. Muralidharan, P.-S. Hou, E. S. Monuki, H.-C. Kuo, V. Rema, et al. (2013)
PNAS 110, E4913-E4921
   Abstract »    Full Text »    PDF »
The Doublesex Homolog Dmrt5 is Required for the Development of the Caudomedial Cerebral Cortex in Mammals.
A. Saulnier, M. Keruzore, S. De Clercq, I. Bar, V. Moers, D. Magnani, T. Walcher, C. Filippis, S. Kricha, D. Parlier, et al. (2013)
Cereb Cortex 23, 2552-2567
   Abstract »    Full Text »    PDF »
LHX2 regulates the neural differentiation of human embryonic stem cells via transcriptional modulation of PAX6 and CER1.
P.-S. Hou, C.-Y. Chuang, C.-F. Kao, S.-J. Chou, L. Stone, H.-N. Ho, C.-L. Chien, and H.-C. Kuo (2013)
Nucleic Acids Res. 41, 7753-7770
   Abstract »    Full Text »    PDF »
Tumor suppressor Nf2 limits expansion of the neural progenitor pool by inhibiting Yap/Taz transcriptional coactivators.
A. Lavado, Y. He, J. Pare, G. Neale, E. N. Olson, M. Giovannini, and X. Cao (2013)
Development 140, 3323-3334
   Abstract »    Full Text »    PDF »
Neurog2 Simultaneously Activates and Represses Alternative Gene Expression Programs in the Developing Neocortex.
C. Kovach, R. Dixit, S. Li, P. Mattar, G. Wilkinson, G. E. Elsen, D. M. Kurrasch, R. F. Hevner, and C. Schuurmans (2013)
Cereb Cortex 23, 1884-1900
   Abstract »    Full Text »    PDF »
Lhx2 Balances Progenitor Maintenance with Neurogenic Output and Promotes Competence State Progression in the Developing Retina.
P. J. Gordon, S. Yun, A. M. Clark, E. S. Monuki, L. C. Murtaugh, and E. M. Levine (2013)
J. Neurosci. 33, 12197-12207
   Abstract »    Full Text »    PDF »
Bone Morphogenic Protein Signaling Is a Major Determinant of Dentate Development.
Y. Choe, A. Kozlova, D. Graf, and S. J. Pleasure (2013)
J. Neurosci. 33, 6766-6775
   Abstract »    Full Text »    PDF »
LHX2 Is Necessary for the Maintenance of Optic Identity and for the Progression of Optic Morphogenesis.
A. Roy, J. de Melo, D. Chaturvedi, T. Thein, A. Cabrera-Socorro, C. Houart, G. Meyer, S. Blackshaw, and S. Tole (2013)
J. Neurosci. 33, 6877-6884
   Abstract »    Full Text »    PDF »
Lmo4 Establishes Rostral Motor Cortex Projection Neuron Subtype Diversity.
G. Y. Cederquist, E. Azim, S. J. Shnider, H. Padmanabhan, and J. D. Macklis (2013)
J. Neurosci. 33, 6321-6332
   Abstract »    Full Text »    PDF »
Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects.
Z. A. Abdelhamed, G. Wheway, K. Szymanska, S. Natarajan, C. Toomes, C. Inglehearn, and C. A. Johnson (2013)
Hum. Mol. Genet. 22, 1358-1372
   Abstract »    Full Text »    PDF »
Transcriptional Analysis of Gli3 Mutants Identifies Wnt Target Genes in the Developing Hippocampus.
K. Hasenpusch-Theil, D. Magnani, E.-M. Amaniti, L. Han, D. Armstrong, and T. Theil (2012)
Cereb Cortex 22, 2878-2893
   Abstract »    Full Text »    PDF »
Pharyngeal mesoderm regulatory network controls cardiac and head muscle morphogenesis.
I. Harel, Y. Maezawa, R. Avraham, A. Rinon, H.-Y. Ma, J. W. Cross, N. Leviatan, J. Hegesh, A. Roy, J. Jacob-Hirsch, et al. (2012)
PNAS 109, 18839-18844
   Abstract »    Full Text »    PDF »
BMP4 Sufficiency to Induce Choroid Plexus Epithelial Fate from Embryonic Stem Cell-Derived Neuroepithelial Progenitors.
M. Watanabe, Y.-J. Kang, L. M. Davies, S. Meghpara, K. Lau, C.-Y. Chung, J. Kathiriya, A.-K. Hadjantonakis, and E. S. Monuki (2012)
J. Neurosci. 32, 15934-15945
   Abstract »    Full Text »    PDF »
Prox1 postmitotically defines dentate gyrus cells by specifying granule cell identity over CA3 pyramidal cell fate in the hippocampus.
T. Iwano, A. Masuda, H. Kiyonari, H. Enomoto, and F. Matsuzaki (2012)
Development 139, 3051-3062
   Abstract »    Full Text »    PDF »
Lhx2-dependent specification of olfactory sensory neurons is required for successful integration of olfactory, vomeronasal, and GnRH neurons.
A. Berghard, A.-C. Hagglund, S. Bohm, and L. Carlsson (2012)
FASEB J 26, 3464-3472
   Abstract »    Full Text »    PDF »
Modeling human cortical development in vitro using induced pluripotent stem cells.
J. Mariani, M. V. Simonini, D. Palejev, L. Tomasini, G. Coppola, A. M. Szekely, T. L. Horvath, and F. M. Vaccarino (2012)
PNAS 109, 12770-12775
   Abstract »    Full Text »    PDF »
Wnt Signaling and Forebrain Development.
S. J. Harrison-Uy and S. J. Pleasure (2012)
Cold Spring Harb Perspect Biol 4, a008094
   Abstract »    Full Text »    PDF »
Tlx1/3 and Ptf1a Control the Expression of Distinct Sets of Transmitter and Peptide Receptor Genes in the Developing Dorsal Spinal Cord.
Z. Guo, C. Zhao, M. Huang, T. Huang, M. Fan, Z. Xie, Y. Chen, X. Zhao, G. Xia, J. Geng, et al. (2012)
J. Neurosci. 32, 8509-8520
   Abstract »    Full Text »    PDF »
The Lhx2 Transcription Factor Controls Thalamocortical Axonal Guidance by Specific Regulation of Robo1 and Robo2 Receptors.
P. Marcos-Mondejar, S. Peregrin, J. Y. Li, L. Carlsson, S. Tole, and G. Lopez-Bendito (2012)
J. Neurosci. 32, 4372-4385
   Abstract »    Full Text »    PDF »
Transcription factor Lhx2 is necessary and sufficient to suppress astrogliogenesis and promote neurogenesis in the developing hippocampus.
L. Subramanian, A. Sarkar, A. S. Shetty, B. Muralidharan, H. Padmanabhan, M. Piper, E. S. Monuki, I. Bach, R. M. Gronostajski, L. J. Richards, et al. (2011)
PNAS 108, E265-E274
   Abstract »    Full Text »    PDF »
Restoring eye size in Astyanax mexicanus blind cavefish embryos through modulation of the Shh and Fgf8 forebrain organising centres.
K. Pottin, H. Hinaux, and S. Retaux (2011)
Development 138, 2467-2476
   Abstract »    Full Text »    PDF »
A Lifespan Analysis of Intraneocortical Connections and Gene Expression in the Mouse II.
C. A. Dye, H. El Shawa, and K. J. Huffman (2011)
Cereb Cortex 21, 1331-1350
   Abstract »    Full Text »    PDF »
Genomic Selection Identifies Vertebrate Transcription Factor Fezf2 Binding Sites and Target Genes.
L. Chen, J. Zheng, N. Yang, H. Li, and S. Guo (2011)
J. Biol. Chem. 286, 18641-18649
   Abstract »    Full Text »    PDF »
In vitro generation of HSC-like cells from murine ESCs/iPSCs by enforced expression of LIM-homeobox transcription factor Lhx2.
K. Kitajima, K.-i. Minehata, K. Sakimura, T. Nakano, and T. Hara (2011)
Blood 117, 3748-3758
   Abstract »    Full Text »    PDF »
FGF8 acts as a classic diffusible morphogen to pattern the neocortex.
R. Toyoda, S. Assimacopoulos, J. Wilcoxon, A. Taylor, P. Feldman, A. Suzuki-Hirano, T. Shimogori, and E. A. Grove (2010)
Development 137, 3439-3448
   Abstract »    Full Text »    PDF »
The Influence of the Environment on Cajal-Retzius Cell Migration.
M. L. Ceci, L. Lopez-Mascaraque, and J. A. de Carlos (2010)
Cereb Cortex 20, 2348-2360
   Abstract »    Full Text »    PDF »
The same enhancer regulates the earliest Emx2 expression in caudal forebrain primordium, subsequent expression in dorsal telencephalon and later expression in the cortical ventricular zone.
Y. Suda, K. Kokura, J. Kimura, E. Kajikawa, F. Inoue, and S. Aizawa (2010)
Development 137, 2939-2949
   Abstract »    Full Text »    PDF »
LIM-Homeobox Gene Lhx5 Is Required for Normal Development of Cajal-Retzius Cells.
A. Miquelajauregui, A. Varela-Echavarria, M. L. Ceci, F. Garcia-Moreno, I. Ricano, K. Hoang, D. Frade-Perez, C. Portera-Cailliau, E. Tamariz, J. A. De Carlos, et al. (2010)
J. Neurosci. 30, 10551-10562
   Abstract »    Full Text »    PDF »
Differential Expression of LIM-Homeodomain Factors in Cajal-Retzius Cells of Primates, Rodents, and Birds.
A. Abellan, A. Menuet, C. Dehay, L. Medina, and S. Retaux (2010)
Cereb Cortex 20, 1788-1798
   Abstract »    Full Text »    PDF »
Zbtb20-Induced CA1 Pyramidal Neuron Development and Area Enlargement in the Cerebral Midline Cortex of Mice.
J. V. Nielsen, J. B. Blom, J. Noraberg, and N. A. Jensen (2010)
Cereb Cortex 20, 1904-1914
   Abstract »    Full Text »    PDF »
NFIA Controls Telencephalic Progenitor Cell Differentiation through Repression of the Notch Effector Hes1.
M. Piper, G. Barry, J. Hawkins, S. Mason, C. Lindwall, E. Little, A. Sarkar, A. G. Smith, R. X. Moldrich, G. M. Boyle, et al. (2010)
J. Neurosci. 30, 9127-9139
   Abstract »    Full Text »    PDF »
Lmx1a regulates fates and location of cells originating from the cerebellar rhombic lip and telencephalic cortical hem.
V. V. Chizhikov, A. G. Lindgren, Y. Mishima, R. W. Roberts, K. A. Aldinger, G. R. Miesegaes, D. S. Currle, E. S. Monuki, and K. J. Millen (2010)
PNAS 107, 10725-10730
   Abstract »    Full Text »    PDF »
Bone Morphogenetic Protein Signaling in the Developing Telencephalon Controls Formation of the Hippocampal Dentate Gyrus and Modifies Fear-Related Behavior.
G. Caronia, J. Wilcoxon, P. Feldman, and E. A. Grove (2010)
J. Neurosci. 30, 6291-6301
   Abstract »    Full Text »    PDF »
Lhx2 links the intrinsic and extrinsic factors that control optic cup formation.
S. Yun, Y. Saijoh, K. E. Hirokawa, D. Kopinke, L. C. Murtaugh, E. S. Monuki, and E. M. Levine (2009)
Development 136, 3895-3906
   Abstract »    Full Text »    PDF »
Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis.
S. S. Choi, A. Omenetti, R. P. Witek, C. A. Moylan, W.-K. Syn, Y. Jung, L. Yang, D. L. Sudan, J. K. Sicklick, G. A. Michelotti, et al. (2009)
Am J Physiol Gastrointest Liver Physiol 297, G1093-G1106
   Abstract »    Full Text »    PDF »
The Rfx4 Transcription Factor Modulates Shh Signaling by Regional Control of Ciliogenesis.
A. M. Ashique, Y. Choe, M. Karlen, S. R. May, K. Phamluong, M. J. Solloway, J. Ericson, and A. S. Peterson (2009)
Science Signaling 2, ra70
   Abstract »    Full Text »    PDF »
Mechanisms Underlying the Specification, Positional Regulation, and Function of the Cortical Hem.
L. Subramanian and S. Tole (2009)
Cereb Cortex 19, i90-i95
   Abstract »    Full Text »    PDF »
Regulatory logic of neuronal diversity: Terminal selector genes and selector motifs.
O. Hobert (2008)
PNAS 105, 20067-20071
   Abstract »    Full Text »    PDF »
A Crucial Role for Primary Cilia in Cortical Morphogenesis.
M. A. Willaredt, K. Hasenpusch-Theil, H. A. R. Gardner, I. Kitanovic, V. C. Hirschfeld-Warneken, C. P. Gojak, K. Gorgas, C. L. Bradford, J. Spatz, S. Wolfl, et al. (2008)
J. Neurosci. 28, 12887-12900
   Abstract »    Full Text »    PDF »
Specific Glial Populations Regulate Hippocampal Morphogenesis.
G. Barry, M. Piper, C. Lindwall, R. Moldrich, S. Mason, E. Little, A. Sarkar, S. Tole, R. M. Gronostajski, and L. J. Richards (2008)
J. Neurosci. 28, 12328-12340
   Abstract »    Full Text »    PDF »
Chip Is Required for Posteclosion Behavior in Drosophila.
P. Hari, M. Deshpande, N. Sharma, N. Rajadhyaksha, N. Ramkumar, K.-i. Kimura, V. Rodrigues, and S. Tole (2008)
J. Neurosci. 28, 9145-9150
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882