Orly Reiner

The Bernstein-Mason Professor of Neurochemistry

Room: 415

Building: Arnold R. Meyer Institute of Biological Sciences

Tel: 972-8-934-4927

Fax: 972-8-934-4108

e-mail: orly.reiner@weizmann.ac.il

 





Human Neuronal Migration Genes: Understanding the Development of Cortical Structure through Analysis of Genes Involved in Lissencephaly

Cortical lamination in humans occurs over months of prenatal development. The final proper layer formation relies on an intricate balance between events of cell cycle, proliferation, neuronal path finding, migration and others. The lissencephaly syndromes in humans involve abnormal cortical lamination and are medically categorized as neuronal migration defects.

The work in our laboratory is focused on genes involved in lissencephaly. The first lissencephaly gene cloned was LIS1 , deletions or mutations in one allele of this gene are sufficient to cause lissencephaly type I. LIS1 is a multifunctional protein, found to interact with tubulin and to influence microtubules dynamics.

It has also been cloned independently as a noncatalytic subunit of platelet-activating factor acetylhydrolase (PAF-AH). An additional interaction described is with the mammalian homolog of NudC, a gene involved in nuclear migration pathway in Aspergillus nidulans . LIS1 expression during development as well as the brain phenotype in lissencephaly patients suggested a role in neuronal migration.

We have created a mouse model for lissencephaly through gene targeting of the murine LIS1 homolog. A second lissencephaly type I gene was identified and mapped to the X chromosome. This gene was cloned recently by two groups in the U.S.A. and France and dubbed doublecortin .

As a result of random X-inactivation, affected females heterozygous for the X-linked mutation show a milder phenotype with bilateral plates or bands of gray matter located beneath the cortex and ventricle but separated from both, hence the descriptive term double cortex, also known as subcortical laminar heterotopia. Doublecortin is highly expressed during brain development, however its function is as yet unknown.

In order to study the function of Doublecortin, we have used an overexpression approach in non-neuronal COS cells. Doublecortin was found to bind to the microtubule cytoskeleton. In vitro and in vivo assays demonstrate that Doublecortin stabilizes microtubules and causes bundling.

The results obtained in this study with Doublecortin and our previous work with LIS1 emphasize the central role of regulation of microtubule dynamics and stability during neuronal morphogenesis.

 

Recent References

Bi* W, Sapir* T, Shchelochkov* OA, Zhang F, Withers MA, Hunter JV, Levy T, Shinder V, Peiffer DA, Gunderson KL, Nezarati MM, Ann Shotts V, Amato SS, Savage SK, Harris DJ, Day-Salvatore DL, Horner M, Lu XY, Sahoo T, Yanagawa
Y, Beaudet AL, Cheung SW, Martinez S, Lupski JR, Reiner O. 2009. Increased LIS1 expression affects human and mouse brain development. Nat Genet. 2009 Jan 11. [Epub ahead of print]

Sapir T, Shmueli A, Levy T, Timm T, Elbaum M, Mandelkow EM, Reiner O. 2008.Antagonistic Effects of Doublecortin and MARK2/Par-1 in the Developing Cerebral Cortex. J Neurosci. 28:13008-13013.

Gorelik, A., Sapir, T., and Reiner, O. 2008. Gene-trap; an antibody dependent approach for verifying integration in your favorite gene.Cellular & Moleular Biology Letters 13:614-620

Sapir, T., Sapoznik, S., Levy, T., Finkelshtein, D., Shmueli, A., Timm,  T., Mandelkow, E.-M., and Reiner, O. 2008. Novel roles of the polarity  kinase MARK2/Par-1 in migrating cortical neurons. J Neurosci 28:5710-5720. [preview]

Gerliz, G., Livnat, I., Ziv, C., Yarden, Y., Bustin, M., and Reiner, O.  2007. Migration Cues Induce Chromatin Alterations. Traffic 8:1521-1529 

Cohen, D., Segal, M., and Reiner, O. Doublecortin supports the development  of dendritic arbors in primary hippocampal neurons. 2008. Dev Neurosci  30:187-199.

Valdés-Sánchez, L., Escámez, T., Echevarria, D., Tabarés, R. Reiner, O.,  Martinez, S., and Geijo-Barrientos, E. 2007. Postnatal alterations of the  inhibitory synaptic responses recorded from cortical pyramidal neurons in the Lis1/sLis1 mutant mouse. MCN 35:220-229

Reiner, O., Coquelle, F.M., Peter, B., Levy, T., Kaplan, A., Sapir, T., Orr,  I., Barkai, N., Eichele, G., and Bergman, S. The evolving doublecortin (DCX) superfamily. 2006. BMC genomics Jul 26;7(1):188.

Coquelle, F.M., Levy, T., Bergman, S. Grayer-Wolf, S., Bar-El, D., Sapir,  T., Brody, Y., Orr, I., Barkai, N., Eichele, G., and Reiner, O. Common and  Divergent roles for members of the mouse DCX superfamily. 2006. Cell Cycle  5:976-983.

Reiner, O., Sapoznik, S., and Sapir, T. 2006. Lissencephaly 1 (LIS1) Linking to Multiple Diseases: Mental Retardation, Neurodegeneration, Schizophrenia, Male Sterility, and More. Neuromolecular Med. 8:547-566.

Reiner, O., and Sapir, T. 2006. Cdk5 checks p27(kip1) in neuronal migration. Nat Cell Biol. 8:11-13.

Reiner, O, and Coquelle, F.M. 2005. Missense mutations resulting in  Type 1 lissencephaly. CMLS 62:425-434.

Shmueli, A., Gdalyahu, A., Sapoznik, S., Sapir, T., Tsukada, M., and Reiner, O. Site-specific dephosphorylation of Doublecortin (DCX) by Protein  Phosphatase 1 (PP1). 2006. MCN 32:15-36.

Tabarés-Seisdedos. R., Escámez, T., Martínez-Giménez, JA., Balanzá, V,  Salazar, J., Selva, G., Rubio, C., Vieta, E., Martínez-Arán, A., Leal, C.,  Gómez-Beneyto, M.,  Reiner, O.,  Martínez, S. Mutations in genes regulating  neuronal migration predict reduced prefrontal neurocognition in  schizophrenia and bipolar disorder. 2006. Neuroscience 139:1289-1300.

Shu, T., Tseng*,H-C., Sapir*, T., Stern, P., Zhou, Y., Sanada, K., Fischer, A., Coquelle, F.M., Reiner, O., Tsai, L.-H., Doublecortin-like Kinase  controls neurogenesis by regulating mitotic spindles and M-phase  progression. 2006. Neuron 49:25-39.

Gerlitz, G., Darhin, E., Giorgio, G., Franco, B., and Reiner, O. Novel Functional Features of the LIS-H Domain: Role in Protein Dimerization, Half-Life and Cellular Localization. 2005. Cell Cycle 4:1632-1640.

Reiner, O. Sapir, t. (2005) Similarities and Differences Between the Wnt and Reelin Pathways in the Forming Brain. Mol Neurobiol. 31(1-3):117-34.

Jimenez-Mateos EM, Wandosell F, Reiner O, Avila J, Gonzalez-Billault C. (2005) Binding of microtubule-associated protein 1B to LIS1 affects the interaction between dynein and LIS1. Biochem J. 389(2):333-341.

Reiner, O. and Coquelle, F.M. (2005) Missense mutations resulting in type 1 lissencephaly. Cell. Mol. life. Sci. 62(4): 425-434.

Epie, N., Ammosova, T., Sapir, T., Voloshin, Y., Lane, W.S., Turner, W., Reiner, O. and Nekhai, S. (2005) HIV-1 Tat interacts with LIS1 protein. Retrovirology 2(1):6 .

Kim, MH., Cooper, DR., Olesky, A., Devedjiev, Y., Derewenda, U., Reiner, O., Otlewski, J. and Derewenda, ZS. 2004. The structure of the N-terminal domain of the product of the lissencephaly gene Lis1 and its functional implications. Structure (Camb.). 12(6): 987-998.

Reiner, O., Gdalyahu, A., Ghosh, I., Levy, T., Sapoznik, S., Nir, R. and Sapir, T. 2004. DCX's, phosphorylation by not just another kinase (JNK). Cell Cycle. 3(6): 747-751.

Gdalyahu, A., Ghosh, I., Levy, T., Sapir, T., Sapoznik, S., Fishler, Y., Azoulai, D. and Reiner, O. 2004. DCX, a new mediator of the JNK pathway. EMBO J. 23(4):823-32.

Caspi, M., Coquelle, F.M., Koifman, C., Levy, T., Arai, H., Aoki, J., De Mey, J.R. and Reiner, O. 2003. LIS1 missense mutations: Variable Phenotypes Result from Unpredictable Alterations in Biochemical and Cellular Properties. J Biol Chem. 278(40): 38740-38748.

Coquelle, F.M., Caspi, M., Cordelieres, F.P., Dompierre, J.P., Dujardin, D.L., Koifman, C., Martin, P., Hoogenraad, C.C., Akhmanova, A., Galjart, N., De Mey, J.R. and Reiner, O. 2002. LIS1, CLIP-170's key to the dynein/dynactin pathway. Mol. Cell. Biol. 22(9): 3089-3102.

Burgess, H.A. and Reiner, O. 2002. Alternative splice variants of doublecortin-like kinase are differentially expressed and have different kinase activities. J. Biol. Chem. 277(20): 17696-17705.

Reiner, O., Cahana A., Escamez, T. and Martinez S. 2002. LIS1- no more no less. Mol. Psychiatry 7(1): 12-6. Review.

Burgess, H.A. and Reiner, O. 2001. Cleavage of doublecortin-like kinase by calpain releases an active kinase fragment from a microtubule anchorage domain. J. Biol. Chem. 276(39): 36397-36403.

Cahana, A., Escamez, T., Nowakowski, R.S., Hayes, N.L., Giacobini, M., Von Holst, A., Shmueli, O., Sapir, T., McConnell, S.K., Wurst, W., Martinez, S. and Reiner O. 2001. Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization. Proc. Natl. Acad. Sci. USA. 98(11): 6429-6434.

Shmueli, O., Gdalyahu, A., Sorokina, K., Nevo, E., Avivi, A. and Reiner O. 2001. DCX in PC12 cells: CREB-mediated transcription and neurite outgrowth. Hum. Mol. Genet. 15;10 (10): 1061-70.

Reiner O. 2000. LIS1: Let's Interact Sometimes ... (part 1). Neuron, 28(3): 633-636.

Caspi, M., Atlas, R., Kantor, A., Sapir, T. and Reiner, O. 2000. Interaction between LIS1 and Doublecortin, two Lissencephaly gene products. Hum. Mol. Genet., 9: 2205-2213.

Burgess, H.A. and Reiner, O. 2000. Doublecortin-like Kinase, is a Microtubule-Associated Protein Kinase Expressed in Growth Cones. MCN, 16: 529-541.

Sapir, T., Horesh, D., Caspi, M., Atlas, R., Burgess, H.A., Grayer Wolf, S., Francis, F., Chelly, J., Elbaum, M., Pietrokovski, S. and Reiner, O. 2000. Doublecortin Mutations Cluster in Evolutionary Conserved Functional Domains. Hum. Mol. Genet. 5: 703-712.

Sheffield, P., Garrard, S., Caspi, M., Aoki, J., Inoue, K., Derewenda, U., Suter, B., Reiner, O. and Derewenda, Z.S. 2000. Homologues of the a - and b -subunits of mammalian brain platelet-activating factor acetylhydrolase Ib in the Drosophila melanogaster genome. Proteins 39: 1-8.

Shmueli, O. and Reiner, O. 2000. Expression of chLIS1, a Chicken Homolog of LIS1. Dev. Genes Evol. 210: 51-54.

Reiner, O. 1999. The unfolding story of two lissencephaly genes and brain development. Molecular neurobiology, 20(2-3): 143-156.

Sapir, T., Eisenstein, M., Burgess, H.A., Horesh, D., Cahana, A., Aoki, J., Hattori, M., Arai, H., Inoue, K., and Reiner, O. 1999. Analysis of Lissencephaly causing LIS1 mutations. Eur. J. Biochem. 266:1011-1020.

Sapir, T., Cahana, A., Seger, R., Nekhai, S. and Reiner, O. 1999. LIS1 is a Microtubule Associated Phosphoprotein. Eur. J. Biochem. 265: 181-188.

Burgess, H., Martinez, S. and Reiner, O. 1999. KIAA0369, Doublecortin-like Kinase,is Expressed during Brain Development. J. Neurosci. Res. 58: 567-575.

Francis, F., Koulakoff, A., Chafey, P., Vinet, M.C., Schaar, B., Boucher, D., Billuart, P., Reiner, O., Kahn, A., Denoulet, P., McConnell, S.K., Berwald-Netter, Y. and Chelly, J. 1999. Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating neurons. Neuron 23: 247-256.

Horesh, D., Sapir, T., Francis, F., Grayer Wolf, S., Caspi, M., Elbaum, M., Chelly, J. and Reiner, O. 1999. Doublecortin, a stabilizer of microtubules. Hum. Mol. Genet. 8: 1599-1610

Cahana, A. and Reiner, O. 1999. Platelet-Activating Factor Acetylhydrolase (Ib),catalytic subunits, expression in the mouse oocyte and zygote. FEBS Letts 451: 99-102.

Sapir, T., Elbaum, M. and Reiner, O. 1997. The Lissencephaly 1 (LIS1) Gene Product Interacts With Tubulin and Reduces Microtubule Catastrophe Events. EMBO J. 16: 6977-6984.

Reiner, O., Albrecht, U., Gordon, M., Chianese, K.A., Wong, C., Sapir, T., Siracusa, L.D., Buchberg, A.M., Caskey, C.T. and Eichele, G. 1995. Lissencephaly gene (LIS1) expression in the CNS suggests a role in neuronal migration. J. Neuroscience 15: 3730-3738.

Reiner, O., Carrozo, R., Shen, Y., Whenert, M., Faustinella, F., Dobyns, W.B., Caskey, C.T. and Ledbetter, D.H. 1993. Isolation of a Miller-Dieker lissencephaly gene containing G protein b -subunit-like repeats. Nature 364: 717-721.

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Department of Molecular Genetics
Weizmann Institute of Science
Rehovot
Israel

Tel: 972-8-934-3970
Fax: 972-8-934-4108

e-mail: Karni.Hertz@weizmann.ac.il

Last Updated: 10 August 2008