The role of ARX in cortical development

The ARX protein (encoded by the aristaless‐related homeobox gene) is a member of the paired class of homeoproteins. More precisely, it is a member of the Aristaless subclass of proteins with a glutamine residue (Q) at the critical position 50 of the homeodomain (Q50). Through identification of diverse inherited or de novo mutations, genetic investigations of X‐linked mental retardation conditions have demonstrated the implication of ARXin a wide spectrum of disorders extending from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of X‐linked mental retardation without apparent brain abnormalities. These investigations have recently directed attention to the role of this gene in brain development. Analysis of its spatiotemporal localization profile have revealed expression mainly in telencephalic structures at all stages of development. Interestingly, in adult, ARX expression becomes restricted to a population of GABAergic neurons. Although the identification of the target genes regulated by ARX remains a crucial step to better understanding its role during brain development, studies of the role of ARX orthologs in different models have indicated that it is essential for important developmental processes such as proliferation, cell differentiation and neuronal migration.

[1]  J. Manley,et al.  Functional domains of the Drosophila Engrailed protein. , 1993, The EMBO journal.

[2]  A. Simeone,et al.  Orthopedia, a novel homeobox-containing gene expressed in the developing CNS of both mouse and drosophila , 1994, Neuron.

[3]  S. Mcconnell,et al.  Cleavage orientation and the asymmetric inheritance of notchl immunoreactivity in mammalian neurogenesis , 1995, Cell.

[4]  T Takahashi,et al.  The Leaving or Q Fraction of the Murine Cerebral Proliferative Epithelium: A General Model of Neocortical Neuronogenesis , 1996, The Journal of Neuroscience.

[5]  Kentaro Kato,et al.  Expression of a novel aristaless related homeobox gene ‘Arx’ in the vertebrate telencephalon, diencephalon and floor plate , 1997, Mechanisms of Development.

[6]  Leyuan Shi,et al.  Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes. , 1997, Science.

[7]  T. Halonen,et al.  Decrease in somatostatin-immunoreactive neurons in the rat amygdaloid complex in a kindling model of temporal lobe epilepsy , 1997, Epilepsy Research.

[8]  A. Goriely,et al.  Drosophila Goosecoid requires a conserved heptapeptide for repression of paired-class homeoprotein activators. , 1998, Development.

[9]  A. Lavdas,et al.  The Medial Ganglionic Eminence Gives Rise to a Population of Early Neurons in the Developing Cerebral Cortex , 1999, The Journal of Neuroscience.

[10]  O. Marín,et al.  Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum. , 1999, Development.

[11]  A. Beverdam,et al.  Vertebrate aristaless-related genes. , 1999, The International journal of developmental biology.

[12]  W. Dobyns,et al.  X-linked lissencephaly with absent corpus callosum and ambiguous genitalia. , 1999, American journal of medical genetics.

[13]  John G. Parnavelas,et al.  The origin and migration of cortical neurones: new vistas , 2000, Trends in Neurosciences.

[14]  P. Beachy,et al.  Genetics of ventral forebrain development and holoprosencephaly. , 2000, Current opinion in genetics & development.

[15]  Kathleen J. Millen,et al.  The mouse Dreher gene Lmx1a controls formation of the roof plate in the vertebrate CNS , 2000, Nature.

[16]  Chris J. McBain,et al.  Interneurons unbound , 2001, Nature Reviews Neuroscience.

[17]  G. Fishell,et al.  In utero fate mapping reveals distinct migratory pathways and fates of neurons born in the mammalian basal forebrain. , 2001, Development.

[18]  S. Anderson,et al.  Distinct cortical migrations from the medial and lateral ganglionic eminences. , 2001, Development.

[19]  T. Weissman,et al.  Neurons derived from radial glial cells establish radial units in neocortex , 2001, Nature.

[20]  H. Okano,et al.  Asymmetric Inheritance of Radial Glial Fibers by Cortical Neurons , 2001, Neuron.

[21]  G. Fishell,et al.  Telencephalic cells take a tangent: non-radial migration in the mammalian forebrain , 2001, Nature Neuroscience.

[22]  O. Hobert,et al.  The lin-11 LIM homeobox gene specifies olfactory and chemosensory neuron fates in C. elegans. , 2001, Development.

[23]  Michel Baulac,et al.  First genetic evidence of GABAA receptor dysfunction in epilepsy: a mutation in the γ2-subunit gene , 2001, Nature Genetics.

[24]  Wei-Yang Lu,et al.  Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy , 2002, Nature Genetics.

[25]  I. Scheffer,et al.  Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX , 2002, Brain and Development.

[26]  Steven Petrou,et al.  Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. , 2002, American journal of human genetics.

[27]  W. Dobyns,et al.  Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans , 2002, Nature Genetics.

[28]  J. Fryns,et al.  ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. , 2002, Human molecular genetics.

[29]  Stéphane Marret,et al.  X‐linked lissencephaly with absent corpus callosum and ambiguous genitalia (XLAG): Clinical, magnetic resonance imaging, and neuropathological findings , 2002, Annals of neurology.

[30]  I. Scheffer,et al.  Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy , 2002, Nature Genetics.

[31]  D. Geschwind,et al.  Human ARX gene: genomic characterization and expression. , 2002, Molecular genetics and metabolism.

[32]  M. Ekker,et al.  Expression from a Dlx gene enhancer marks adult mouse cortical GABAergic neurons. , 2002, Cerebral cortex.

[33]  H. El-Hodiri,et al.  The Xenopus arx gene is expressed in the developing rostral forebrain , 2002, Development Genes and Evolution.

[34]  I. Scheffer,et al.  X-linked myoclonic epilepsy with spasticity and intellectual disability: Mutation in the homeobox gene ARX , 2002, Neurology.

[35]  F. Mascagni,et al.  Immunohistochemical characterization of somatostatin containing interneurons in the rat basolateral amygdala , 2002, Brain Research.

[36]  J. Winkler,et al.  ARX mutations in X-linked lissencephaly with abnormal genitalia , 2003, Neurology.

[37]  O. Marín,et al.  Cell migration in the forebrain. , 2003, Annual review of neuroscience.

[38]  J. Parnavelas,et al.  Lhx6 Regulates the Migration of Cortical Interneurons from the Ventral Telencephalon But Does Not Specify their GABA Phenotype , 2004, The Journal of Neuroscience.

[39]  J. Gécz,et al.  Mouse orthologue of ARX, a gene mutated in several X‐linked forms of mental retardation and epilepsy, is a marker of adult neural stem cells and forebrain GABAergic neurons , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[40]  J. Gleeson,et al.  Cortical neuronal migration mutants suggest separate but intersecting pathways. , 2004, Annual review of cell and developmental biology.

[41]  J. Knoblich,et al.  Dare to Be Different: Asymmetric Cell Division in Drosophila, C. elegans and Vertebrates , 2004, Current Biology.

[42]  Gábor Szabó,et al.  Preferential origin and layer destination of GAD65-GFP cortical interneurons. , 2004, Cerebral cortex.

[43]  J. Couso,et al.  Chip-mediated partnerships of the homeodomain proteins Bar and Aristaless with the LIM-HOM proteins Apterous and Lim1 regulate distal leg development , 2004, Development.

[44]  H. Van Esch,et al.  Neuroanatomical distribution of ARX in brain and its localisation in GABAergic neurons. , 2004, Brain research. Molecular brain research.

[45]  J. Golden,et al.  A polyalanine tract expansion in Arx forms intranuclear inclusions and results in increased cell death , 2004, The Journal of cell biology.

[46]  E. Zackai,et al.  Mutations of ARX are associated with striking pleiotropy and consistent genotype–phenotype correlation , 2004, Human mutation.

[47]  Nichole L Prescott,et al.  Xenopus aristaless‐related homeobox (xARX) gene product functions as both a transcriptional activator and repressor in forebrain development , 2005, Developmental dynamics : an official publication of the American Association of Anatomists.

[48]  P. Sengupta,et al.  Regulation of chemosensory and GABAergic motor neuron development by the C. elegans Aristaless/Arx homolog alr-1 , 2005, Development.

[49]  Y. Yoshihara,et al.  Arx homeobox gene is essential for development of mouse olfactory system , 2005, Development.

[50]  L. Tsai,et al.  G Protein βγ Subunits and AGS3 Control Spindle Orientation and Asymmetric Cell Fate of Cerebral Cortical Progenitors , 2005, Cell.

[51]  I. Cobos,et al.  The vertebrate ortholog of Aristaless is regulated by Dlx genes in the developing forebrain , 2005, The Journal of comparative neurology.

[52]  Jamel Chelly,et al.  Human disorders of cortical development: from past to present , 2006, The European journal of neuroscience.

[53]  E. Guillén-Navarro,et al.  [Monogenic causes of X-linked mental retardation]. , 2006, Revista de neurologia.