Children's Hospital Boston Research  
HomeLabsResearchDepartments
 


Research
MRRC ProjectsLab Website



Christopher Walsh, MD/PhD
Bullard Professor of Neurology
Harvard Medical School/ Children's Hospital
Beth Israel Deaconess Medical Center
Department of Neurology

 


MRRC Project(s)

R01 NS35129-03
Human Epilepsy Genetics: Neuronal Migration Disorders

R01 NS38097-02
Signal Transduction Pathways for Neuronal Migration

The cerebral cortex is the brain structure that defines us as uniquely human, and which is responsible for all of our higher cognitive functions. Hence, essentially all causes of mental retardation have their effects by somehow disrupting the proper function of the cerebral cortex. Disorders that cause mental retardation include a host of different factors, ranging from genetic disorders that disrupt normal cortical development, to neonatal hypoxic-ischemic injury that damage the maturing cortical cells. Recently, the development of the human genome project has allowed the direct identification of increasing numbers of genes that are required for cortical development. While these genes cause mental retardation, study of the biological function of their gene products potentially gives us insight into the normal development and function of the brain as well.

Research Description

Highlights of Major Accomplishments

  • Delineation of the molecular genetics of the X-linked disorder, bilateral periventricular heterotopia, including mapping of the gene, characterization of the genetic and clinical features of the disorder, identification of filamin 1 as the responsible gene, and insights into probable function of the gene.

  • Definition of the molecular genetics of double cortex syndrome, including definition of the clinical and neuropathologic spectrum (double cortex in females, lissencephaly in males), mapping and then identification of the gene doublecortin, establishment of genotype-phenotype correlations, and characterization of the structure and function of the doublecortin protein.

  • Identification of the gene for an X-linked syndrome of "nonspecific mental retardation", MRX30, and determination that the gene encodes a kinase (PAK3) critical to the control of the cytoskeleton.

Major Results

1. Cell lineage in developing forebrain

2. Molecular genetics of periventricular heterotopia

3. Molecular genetics of neuronal migration

4. Molecular genetics of double cortex syndrome

5. Molecular genetics of an X-linked form of "nonspecific mental retardation"

1. Cell lineage in developing forebrain

Since 1995, we have been continuing previous studies of cell lineage in the developing forebrain. We have found that the cortex is composed of two populations of neurons in terms of their clonal origins. Widespread clones, in which sibling neurons are scattered over much of the area of the cortex, generate a surprisingly large proportion of cortical neurons. However, in addition we have found large clusters of clonally related neurons that can be best seen when clones are labeled at very early developmental stages. While the tendency for some progenitor cells to produce large clusters of clonally related progeny is consistent with a possible role for cell lineage in specification of cerebral cortical regions, the widespread clones suggest that not all neurons can be specified by any lineage-based mechanism.

2. Molecular genetics of periventricular heterotopia

A major focus of our research in the last 5 years has been on the positional cloning of genes required for normal human cortical development and the biological characterization of their function. We started by studying a congenital human malformation, called periventricular heterotopia, in which a large number of cortical neurons fail to migrate normally and cause epilepsy. We mapped the responsible gene and presented the genetic and biological features of the disorder in 1996. Our mapping of the gene for periventricular heterotopia led to the identification of the responsible gene as filamin 1 in 1998. Filamin 1 is expressed both inside and outside the nervous system, and patients with filamin 1 mutations have not only brain malformations but other non-CNS conditions, such as strokes and vascular disorders consistent with filamin 1's other functions in platelets and vascular endothelial cells. In migrating cortical neurons, filamin 1 provides a potential link between the signaling molecules and the actin cytoskeleton. We are presently characterizing the function of filamin 1 in migrating neurons.

3. Molecular genetics of neuronal migration

Parallel to our interests in human genes that regulate neuronal migration to the cerebral cortex, we also studied a mouse mutant with abnormal gait that reflects abnormal cortical neuronal migration (called scrambler). We characterized this mouse in terms of the specific migrational disturbance that affects the cerebral cortex. We also mapped the gene and identified the specific mutation, defining a disruption of a gene called disabled 1. The mouse disabled 1 gene encodes a cytoplasmic phosphoprotein that presumably represents part of a signaling system that steers migrating neurons. This work provided an entry point into the signaling cascade that guides migrating neurons. We are presently studied the signaling cascade in which disabled functions.

4. Molecular genetics of double cortex syndrome

While mapping and analyzing the scrambler mouse and the human periventricular heterotopia syndrome, we established another collaboration to map and clone another X-linked gene that causes an inherited human disorder. This second X-linked gene produces profound neuronal migration arrest in the cortex of males, resulting in mental retardation and epilepsy. Affected females show a milder phenotype in which there is a normal cortex and a second, "double cortex" beneath it, formed by the arrested migration of roughly half of the cortical neurons. After mapping the gene, we identified a single gene, encoding a novel cytoplasmic protein (called doublecortin) as mutated in females with double cortex and in males with X-linked lissencephaly. We have also characterized the patterns of mutations in doublecortin that cause disease, and related these to clinical phenotypes. We have carried out further characterization of the doublecortin protein, and found that it serves as a neuron-specific microtubule-associated protein that functions specifically in migrating neurons and controls microtubule structure.

5. Molecular genetics of an X-linked form of "nonspecific mental retardation"

Our study of the double cortex locus led to identification of another gene highly expressed in the brain of other human diseases that map to the same chromosomal region. We identified the gene for one of these conditions, called MRX30. MRX means "nonspecific mental retardation" and refers to individuals with no stigmata of a genetic condition, yet who suffer from mental retardation or learning difficulties in an inherited, X-linked fashion. MRX genes have long been sought after, since they are likely to be required for changing neural connections in the brain that underlie learning and memory. The MRX30 encodes p21-activated kinase 3 (PAK3); the PAK kinases are critical to the control of the cytoskeleton in many cell types, as they bind G proteins of the Rho GTPase family.

Publications

Eksioglu Y, Scheffer IE, Cardenas P, Knoll J, DiMario F, Ramsby G, Berg M, Kamuro K, Berkovic SF, Duyk GM, Huttenlocher PR, Walsh C. Periventricular heterotopia: an X-linked dominant epilepsy locus causing aberrant cortical development. Neuron 1996; 16:77-87. [cover illustration]

Dobyns WB, Andermann E, Andermann F, Czapansky-Beilman D, Dubeau F, Dulac O, Guerrini R, Hirsch B, Ledbetter DB, Lee NS, Motte J, Pinard J-M, Radtke R, Ross ME, Tampieri D, Walsh CA, Truwit CL. X-linked malformations of neuronal migration. Neurology 1996; 47:331-339.

Walsh C. Neural development: Identical twins separated at birth? Current Biology 1996; 6:26-28.

Reid CB, Walsh CA. Early development of the cerebral cortex. In, Mize RR, Erzurumlu R. eds. Progress in Brain Research, 1996; 108:17-30.

Allen KM and Walsh C. Shaking down new epilepsy genes. Nature Medicine 1996; 2:516-518.

Gleeson JG and Walsh CA. New genetic insights into cerebral cortical development. In: Galaburda A, Christen Y. eds. Normal and Abnormal Development of the Cerebral Cortex. Berlin: Springer-Verlag, 1997; 145-163.

Ross ME, Allen KM, Srivastava AK, Featherstone T, Hirsch B, Harding BN, Abdullah R, Berg ME, Czapansky-Bielman D, Flanders DJ, Gleeson JG, Guerrini R, Motte J, Scheffer I, Berkovic S, King RA, Ledbetter DH, Schlessinger D, Dobyns WB, Walsh CA. Linkage and physical mapping of X-linked lissencephaly/SBH (XLIS): a novel gene causing neuronal migration defects in human brain. Hum Molec Genet 1997; 6:555-563.

Reid CB, Tavazoie SF, Walsh CA. Asymmetric division and clonal dispersion in ferret neocortex. Development 1997; 124:2441-2450.

Gonzàlez JL, Goldowitz D, Sweet HO, Davisson MT, Walsh CA. Birthdate and cell marker analysis of scrambler: a novel mutation affecting cortical development with a reeler-like phenotype. J Neurosci 1997; 17:9204-9211.

Ware ML, Fox JW, Gonzalez JL, Davis NM, Lambert de Rouvroit C, Russo CJ, Chua SC, Jr., Goffinet AM, Walsh, CA. Aberrant splicing of a mouse disabled homologue, mdab1, in the scrambler mouse. Neuron 1997; 19:239-249.

Berg MJ, Schifitto G, Powers JM, Martinez-Capolino C, Fong C-T, Myers GJ, Epstein LG, Walsh CA. X-linked female band heterotopia-male lissencephaly syndrome. Neurology 1998; 1143-1146.

Gleeson JG, Allen KM, Fox JW, Lamperti ED, Berkovic S, Scheffer I, Dobyns WB, Minnerath SR, Ross ME, Walsh, CA. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 1998; 92:62-73. [cover illustration]

Allen KM, Gleeson JG, Shoup SM, Walsh CA. A YAC contig in Xq23, from DXS287 to DXS2088, spanning the critical region for double cortex/X-linked lissencephaly (DC/XLIS). Genomics 1998; 52:214-218.

Pilz DT, Matsumoto N, Minnerath S, Mills P, Gleeson JG, Allen KM, Walsh CA, Barkovich AJ, Dobyns WB, Ledbetter DH, Ross ME. LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Hum Molec Genet 1998; 7:2029-2037.

Allen KM, Gleeson JG, Partington MW, MacMillan JC, Mulley JC, Walsh CA. Mutation in the PAK3 gene in nonsyndromic X-linked mental retardation. Nature Genetics 1998; 20:25-31.

Fox JW, Lamperti ED, Eksioglu YZ, Hong SE, Feng Y, Graham DA, Scheffer IE, Dobyns WB, Hirsch BA, Radtke RA, Berkovic SF, Huttenlocher PR, Walsh CA. Mutations in Filamin 1 arrest migration of cerebral cortical neurons in human periventricular heterotopia. Neuron 1998; 21:1315-1325 [cover illustration].

Walsh, CA. LISsen Up! Nature Genetics 1998; 19:307-308.

Walsh CA. Cell lineage analysis in the central nervous system. Encyclopedia of Neuroscience, Berlin: Elsevier Press, 1998.

Walsh C. Early events in the development of the cerebral cortex. In: Engel J, Pedley TA. eds. Epilepsy: A Comprehensive Textbook, 2nd edition and CD-ROM edition. NY: Lippincott-Raven Publishers, 1998.

Ware ML and Walsh CA. Cell lineage and cell migration in the developing cerebral cortex. In: Moody SA. ed. Cell Fate and Cell Fate Determination. NY: Academic Press, 1999; 529-547.

Walsh, CA. Genetic malformations of the human cerebral cortex. Neuron 1999; 23:19-29.

Fox JW and Walsh CA. Periventricular heterotopia and the genetic control of neuronal migration. Am J Hum Genet 1999; 65:19-24.

Reid CB, Liang I, Walsh, CA. Clonal mixing, clonal restriction, and specification of cell types in the developing rat olfactory bulb. J Comp Neurol 1999; 403:106-118.

Gleeson JG, Minnerath SR, Allen KM, Fox JW, Hong SE, Berg MJ, Kuzniecky R, Reitnauer PJ, Borgatti R, Mira AP, Guerrini R, Holmes GL, Rooney CM, Berkovic S, Scheffer I, Cooper EC, Leroy R, Andermann E, Wheless JW, Dobyns WB, Ross ME, Walsh CA. Characterization of mutations in the gene doublecortin in patients with double cortex syndrome. Ann Neurol 1999; 45:146-53.

Ware ML, Tavasoie S, Reid CB, Walsh CA. Coexistence of widespread clones and large radial clonal patterns in early ferret cortex. Cerebral Cortex 1999; 9:636-645.

Gleeson JG, Lin PT, Flanagan LA, Walsh CA. Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 1999; 23:257-271.

Dobyns WB, Truwit CL, Ross ME, Matsumoto N, Pilz DT, Ledbetter DH, Gleeson JG, Walsh CA, Barkovich AJ. Differences in gyral pattern distinguish chromosome 17-linked lissencephaly and X-linked lissencephaly. Neurology 1999; 53:270-277.

Chenn A, Walsh CA. Perspectives: neurobiology. Cranking it up a notch. Science 1999; 286:689-690.

Allen KM, Walsh CA. Genes that regulate neuronal migration in the cerebral cortex. Epilepsy Research 1999; 36:143-154.

Walsh CA. Genetics of neuronal migration in the cerebral cortex. MRDD Res Rev 2000: 6:34-40.

Feng Y, Olson EC, Stukenberg PT, Flanagan LA, Kirschner MW, Walsh CA. LIS1 regulates CNS lamination by interacting with mNudE, a central component of the centrosome. Neuron 2000; 28:665-679.

Gleeson JG, Walsh CA. Neuronal migration disorders: from genetic diseases to developmental mechanisms. TINS 2000; 352-359.

Gleeson JG, Luo RF, Grant PE, Guerrini R, Huttenlocher PR, Berg MJ, Ricci S, Cusmai R, Wheless JW, Berkovic S, Scheffer I, Dobyns WB, Walsh CA. Genetic and neuroradiological
heterogeneity of double cortex syndrome. Ann Neurol 2000;47:265-269.

Walsh CA, Goffinet AM. Potential mechanisms of mutations that affect neuronal migration in man and mouse. Curr Opin Genet Dev 2000; 10:270-274.

Taylor KR, Holzer AK, Bazan JF, Walsh CA, Gleeson JG. Patient mutations in doublecortin define a repeated tubulin-binding domain. J Biol Chem 2000;275(44):34442-50.

Gleeson JG, Minnerath S, Kuzniecky RI, Dobyns WB, Young ID, Ross ME, Walsh CA. Somatic and germline mosaic mutations in the doublecortin gene are associated with variable phenotypes. Am J Hum Genet 2000;67(3):574-81.

Lin PT, Gleeson JG, Corbo JC, Flanagan L, Walsh CA. DCAMKL1 encodes a protein kinase with homology to doublecortin that regulates microtubule polymerization. J Neurosci 2000;20(24):9152-61.

Wernovsky G, Stiles KM, Gauvreau K, Gentles TL, duPlessis AJ, Bellinger DC, Walsh AZ, Burnett J, Jonas RA, Mayer JE, Jr., Newburger JW. Cognitive development after the Fontan operation. Circulation 2000;102(8):883-9.

Dulabon L, Olson EC, Taglienti M, Eisenhuth S, McGrath B, Walsh CA, Kreidberg JA, Anton ES. Reelin binds a3b1 integrin and inhibits neuronal migration. Neuron 2000;27:33-44.

Olson E, Walsh CA. Smooth, rough and upside down neocortical developmen. Curr Opin Genet Dev 2002;12:320-327.

Walsh CA. Genetic Disorders of Human Cerebral Cortical Development. Adv Clin Neurosci 2002;12:515-527.

Piao X, Basel-Vanagaite L, Straussberg R, Grant PE, Pugh EW, Doheny K, Doan B, Hong SE, Shugart YY, Walsh CA. An Autosomal recessive form of bilateral frontoparietal polymicrogyria (BFPP) maps to chromosome 16 q12.2-21. Am J Hum Genet 2002;70:1028-1033.

Sheen VL, Feng Y, Graham D, Takafuta T, Shapiro SS, Walsh CA. Filamin A and Filamin B are co-expressed within neurons during periods of neuronal migration and can physically interact. Hum Mol Genet 2002;11(23):2845-54.

Bond J, Roberts E, Mochida GH, Hampshire DJ, Scott S, Askham JM, Springell K, Mahadevan M, Crow YJ, Markham AF, Walsh CA, Woods CG. ASPM is a major determinant of cerebral cortical size. Nat Genet 2002;32(2):316-20.

Corbo JC, Deuel TA, Long JM, LaPorte P, Tsai E, Wynshaw-Boris A, Walsh CA. Doublecortin is required in mice for lamination of the hippocampus but not the neocortex. J Neurosci 2002;22(17):7548-57.

Chae TH, Allen KM, Davisson MT, Sweet HO, Walsh CA. Mapping of the mouse hyh gene to a YAC/BAC contig on proximal Chromosome 7. Mamm Genome 2002;13(5):239-44.

Reid CB, Walsh CA. Evidence of common progenitors and patterns of dispersion in rat striatum and cerebral cortex. J Neurosci 2002;22(10):4002-14. 1

Kakita A, Hayashi S, Moro F, Guerrini R, Ozawa T, Ono K, Kameyama S, Walsh CA, Takahashi H. Bilateral periventricular nodular heterotopia due to filamin 1 gene mutation: widespread glomeruloid microvascular anomaly and dysplastic cytoarchitecture in the cerebral cortex. Acta Neuropathol (Berl) 2002;104(6):649-57.

Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, Celli J, van Beusekom E, van der Zwaag B, Kayserili H, Merlini L, Chitayat D, Dobyns WB, Cormand B, Lehesjoki AE, Cruces J, Voit T, Walsh CA, van Bokhoven H, Brunner HG. Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet 2002;71(5):1033-43.

Chenn A, Walsh CA. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 2002;297(5580):365-9.

Olson EC, Walsh CA. Smooth, rough and upside-down neocortical development. Curr Opin Genet Dev 2002;12(3):320-7.

Sheen VL, Topcu M, Berkovic SF, Yalnizoglu D, Blatt I, Bodell A, Hill RS, Ganesh VS, Cherry TJ, Shugart YY, Walsh CA. Autosomal recessive form of periventricular heterotopia. Neurology 2003;60:1108-1112.

Chenn A, Walsh CA. Increased neuronal production, enlarged forebrains and cytoarchitectural distortions in beta-catenin overexpressing transgenic mice. Cereb Cortex 2003;13(6):599-606.

Teillon S, Walsh C. Reelin is expressed in the olfactory system but is not a guidance cue for vomeronasal axons. Dev Brain Res 2003;140:303-307.

Chang BS, Piao X, Bodell A, Basel-Vanagaite L, Straussberg R, Dobyns WB, Qasrawi B, Winter RM, Innes AM, Voit T, Grant PE, Barkovich AJ, Walsh CA. Bilateral frontoparietal polymicrogyria: clinical and radiological features in 10 families with linkage to chromosome 16. Ann Neurol 2003;53(5):596-606.

Zollino M, Colosimo C, Zuffardi O, Rossi E, Tosolini A, Walsh CA, Neri G. Cryptic t(1;12)(q44;p13.3) translocation in a previously described syndrome with polymicrogyria, segregating as an apparently X-linked trait. Am J Med Genet 2003;117:65-71.

Ferland RJ, Cherry TJ, Preware PO, Morrisey EE, Walsh CA. Characterization of Foxp2 and Foxp1 mRNA and protein in the developing and mature brain. J Comp Neurol 2003;460(2):266-79..

Rajab A, Mochida GH, Hill A, Ganesh V, Bodell A, Riaz A, Grant PE, Shugart YY, Walsh CA. A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21. Neurology 2003;60(10):1664-7.

Chang BS, Walsh CA. Mapping form and function in the human brain: the emerging field of functional neuroimaging in cortical malformations. Epilepsy Behav 2003;4(6):618-25.

Sheen VL, Walsh CA. Developmental genetic malformations of the cerebral cortex. Curr Neurol Neurosci Rep 2003;3(5):433-41.

Zollino M, Colosimo C, Zuffardi O, Rossi E, Tosolini A, Walsh CA, Neri G. Cryptic t(1;12)(q44;p13.3) translocation in a previously described syndrome with polymicrogyria, segregating as an apparently X-linked trait. Am J Med Genet 2003;117A(1):65-71.

Teillon SM, Yiu G, Walsh CA. Reelin is expressed in the accessory olfactory system, but is not a guidance cue for vomeronasal axons. Brain Res Dev Brain Res 2003;140(2):303-7.

Sheen VL, Wheless JW, Bodell A, Braverman E, Cotter PD, Rauen KA, Glenn O, Weisiger K, Packman S, Walsh CA, Sherr EH. Periventricular heterotopia associated with chromosome 5p anomalies. Neurology 2003;60(6):1033-6.

Kim MH, Cierpicki T, Derewenda U, Krowarsch D, Feng Y, Devedjiev Y, Dauter Z, Walsh CA, Otlewski J, Bushweller JH, Derewenda ZS. The DCX-domain tandems of doublecortin and doublecortin-like kinase. Nat Struct Biol 2003;10(5):324-33.

Chang BS, Piao X, Bodell A, Basel-Vanagaite L, Straussberg R, Dobyns WB, Qasrawi B, Winter RM, Innes AM, Voit T, Grant PE, Barkovich AJ, Walsh CA. Bilateral frontoparietal polymicrogyria: clinical and radiological features in 10 families with linkage to chromosome 16. Ann Neurol 2003;53(5):596-606.

Lee A, Maldonado M, Baybis M, Walsh CA, Scheithauer B, Yeung R, Parent J, Weiner HL, Crino PB. Markers of cellular proliferation are expressed in cortical tubers. Ann Neurol 2003;53(5):668-73.

Chenn A, Walsh CA. Increased neuronal production, enlarged forebrains and cytoarchitectural distortions in beta-catenin overexpressing transgenic mice. Cereb Cortex 2003;13(6):599-606.

Rajab A, Mochida GH, Hill A, Ganesh V, Bodell A, Riaz A, Grant PE, Shugart YY, Walsh CA. A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21. Neurology 2003;60(10):1664-7.

Bond J, Scott S, Hampshire DJ, Springell K, Corry P, Abramowicz MJ, Mochida GH, Hennekam RC, Maher ER, Fryns JP, Alswaid A, Jafri H, Rashid Y, Mubaidin A, Walsh CA, Roberts E, Woods CG. Protein-Truncating Mutations in ASPM Cause Variable Reduction in Brain Size. Am J Hum Genet 2003;73(6):1170-7.

Sheen VL, Ganesh VS, Topcu M, Sebire G, Bodell A, Hill RS, Grant PE, Shugart YY, Imitola J, Khoury SJ, Guerrini R, Walsh CA. Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex. Nat Genet 2004;36(1):69-76.

Basel-Vanagaite L, Straussberg R, Ovadia H, Kaplan A, Magal N, Shorer Z, Shalev H, Walsh C, Shohat M. Infantile bilateral striatal necrosis maps to chromosome 19q. Neurology 2004;62(1):87-90.

Chae TH, Kim S, Marz KE, Hanson PI, Walsh CA. The hyh mutation uncovers roles for alphaSnap in apical protein localization and control of neural cell fate. Nat Genet 2004;36:264-270.

Piao X, Hill RS, Bodell A, Chang BS, Basel-Vanagaite L, Straussberg R, Dobyns WB, Qasrawi B, Winter RM, Innes AM, Voit T, Ross ME, Michaud JL, Descarie JC, Barkovich AJ, Walsh CA. G protein-coupled receptor-dependent development of human frontal cortex. Science 2004;303(5666):2033-6.

See Dr. Walsh's publications via PubMed

Contact Information

E-mail: Christopher Walsh, MD/PhD
Bullard Professor of Neurology
Harvard Medical School/Children's Hospital
Beth Israel Deaconess Medical Center
Department of Neurology

Lab Members:

Kira Apse, MA - Genetic Counselor
Adria Bodell - Genetic Counselor
Teresa Chae - Graduate Student
Sophie Currier - Graduate Student
Thomas Deuel - Graduate Student
Yuanyi Feng, PhD - Postdoctoral Fellow
Russell Ferland, PhD - Postdoctoral Fellow
Anthony Hill, PhD - Postdoctoral Fellow
R. Sean Hill, PhD - Lab Manager
Seonhee Kim - Postdoctoral Fellow
Sofia Lizarraga - Postdoctoral fellow
Ganesh Mochida, MD
Marta Nieto - Postdoctoral Fellow
Xianhua Piao, MD/PhD
Volney Sheen, MD/PhD - Postdoctoral Fellow
Jun Shen, PhD
Tao Sun - Postdoctoral Fellow
Ian Tietjen - Postdoctoral Fellow
Seung Yun Yoo - Postdoctoral Fellow