Homeobox genes in vertebrate forebrain development and disease

Clinical Genetics

Volumn 73, Issue 3, 2008, Pages 212-226

  Wigle, J T ^a   Eisenstat, David D ^a,b  

^a UNIVERSITY OF MANITOBA   (Canada)

^b UNIVERSITY OF MANITOBA   (Canada)

Author keywords

Arx; Dlx; Emx; Forebrain development; Gsh2; Homeobox genes; Lhx; Nkx2 1; Otx; Pax6; Vax1

Indexed keywords

DNA; GENE PRODUCT; HOMEODOMAIN PROTEIN; PROTEIN VAX; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR DLX1; TRANSCRIPTION FACTOR DLX2; TRANSCRIPTION FACTOR DLX5; TRANSCRIPTION FACTOR DLX6; TRANSCRIPTION FACTOR EMX1; TRANSCRIPTION FACTOR EMX2; TRANSCRIPTION FACTOR GSH2; TRANSCRIPTION FACTOR LHX2; TRANSCRIPTION FACTOR LHX5; TRANSCRIPTION FACTOR LHX6; TRANSCRIPTION FACTOR LHX7; TRANSCRIPTION FACTOR NKX2-1; TRANSCRIPTION FACTOR OTX; TRANSCRIPTION FACTOR PAX6; UNCLASSIFIED DRUG;

BRAIN CELL; BRAIN DEVELOPMENT; BRAIN DISEASE; DNA BINDING; EMBRYO DEVELOPMENT; EPILEPSY; GENE EXPRESSION; GENE FUNCTION; GENE MUTATION; GENETIC ASSOCIATION; GENETIC VARIABILITY; HETEROZYGOSITY; HUMAN; MENTAL DEFICIENCY; MOTOR DYSFUNCTION; NERVOUS SYSTEM DEVELOPMENT; NONHUMAN; PRIORITY JOURNAL; REVIEW; TRANSCRIPTION REGULATION;

ANIMALS; DISEASE; GENES, HOMEOBOX; HOMEODOMAIN PROTEINS; HUMANS; NEURONS; PROSENCEPHALON; VERTEBRATES;

VERTEBRATA;

EID: 38949214667     PISSN: 00099163     EISSN: 13990004     Source Type: Journal    
DOI: 10.1111/j.1399-0004.2008.00967.x     Document Type: Review

References (146)

1. Wigle JT, Eisenstat DD. Common signaling pathways used during development (chapter 21). In: Moore KL, Persaud TVN, eds. The developing human: Clinically oriented embryology, 8th edn. Philadelphia, PA: Elsevier Saunders, 2008: 487-495.
2. Sanes DH, Reh TA, Harris WA. Development of the nervous system. Burlington, MA: Elsevier Academic Press, 2006.
3. Nagy A, Perrimon N, Sandmeyer S et al. Tailoring the genome: The power of genetic approaches. Nat Genet 2003: 33 (Suppl.): 276-284.
4. Wiznerowicz M, Szulc J, Trono D. Tuning silence: Conditional systems for RNA interference. Nat Methods 2006: 3: 682-688.
5. Sawitzke JA, Thomason LC, Costantino N et al. Recombineering: In vivo genetic engineering in E. coli, S. enterica, and beyond. Methods Enzymol 2007: 421: 171-199.
6. Kiecker C, Lumsden A. Compartments and their boundaries in vertebrate brain development. Nat Rev Neurosci 2005: 6: 553-564.
7. Rubenstein JL, Martinez S, Shimamura K et al. The embryonic vertebrate forebrain: The prosomeric model. Science 1994: 266: 578-580.
8. Puelles L, Rubenstein JL. Forebrain gene expression domains and the evolving prosomeric model. Trends Neurosci 2003: 26: 469-476.
9. Sugino K, Hempel CM, Miller MN et al. Molecular taxonomy of major neuronal classes in the adult mouse forebrain. Nat Neurosci 2006: 9: 99-107.
10. Lein ES, Hawrylycz MJ, Ao N et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 2007: 445: 168-176.
11. Molyneaux BJ, Arlotta P, Menezes JR et al. Neuronal subtype specification in the cerebral cortex. Nat Rev Neurosci 2007: 8: 427-437.
12. Wonders CP, Anderson SA. The origin and specification of cortical interneurons. Nat Rev Neurosci 2006: 7: 687-696.
13. Guillemot F. Spatial and temporal specification of neural fates by transcription factor codes. Development 2007: 134: 3771-3780.
14. Gehring WJ, Qian YQ, Billeter M et al. Homeodomain-DNA recognition. Cell 1994: 78: 211-223.
15. Joshi R, Passner JM, Rohs R et al. Functional specificity of a Hox protein mediated by the recognition of minor groove structure. Cell 2007: 131: 530-543.
16. Holland PW, Takahashi T. The evolution of homeobox genes: Implications for the study of brain development. Brain Res Bull 2005: 66: 484-490.
17. Garcia-Fernandez J. The genesis and evolution of homeobox gene clusters. Nat Rev Genet 2005: 6: 881-892.
18. Simeone A, Acampora D, Gulisano M et al. Nested expression domains of four homeobox genes in developing rostral brain. Nature 1992: 358: 687-690.
19. Acampora D, Mazan S, Lallemand Y et al. Forebrain and midbrain regions are deleted in Otx2-/- mutants due to a defective anterior neuroectoderm specification during gastrulation. Development 1995: 121: 3279-3290.
20. Matsuo I, Kuratani S, Kimura C et al. Mouse Otx2 functions in the formation and patterning of rostral head. Genes Dev 1995: 9: 2646-2658.
21. Borgkvist A, Puelles E, Carta M et al. Altered dopaminergic innervation and amphetamine response in adult Otx2 conditional mutant mice. Mol Cell Neurosci 2006: 31: 293-302.
22. Puelles E, Acampora D, Gogoi R et al. Otx2 controls identity and fate of glutamatergic progenitors of the thalamus by repressing GABAergic differentiation. J Neurosci 2006: 26: 5955-5964.
23. Acampora D, Mazan S, Avantaggiato V et al. Epilepsy and brain abnormalities in mice lacking the Otx1 gene. Nat Genet 1996: 14: 218-222.
24. Weimann JM, Zhang YA, Levin ME et al. Cortical neurons require Otx1 for the refinement of exuberant axonal projections to subcortical targets. Neuron 1999: 24: 819-831.
25. Martinez S, Crossley PH, Cobos I et al. FGF8 induces formation of an ectopic isthmic organizer and isthmocerebellar development via a repressive effect on Otx2 expression. Development 1999: 126: 1189-1200.
26. Millet S, Campbell K, Epstein DJ et al. A role for Gbx2 in repression of Otx2 and positioning the mid/hindbrain organizer. Nature 1999: 401: 161-164.
27. Heimbucher T, Murko C, Bajoghli B et al. Gbx2 and Otx2 interact with the WD40 domain of Groucho/Tle corepressors. Mol Cell Biol 2007: 27: 340-351.
28. Kurokawa D, Kiyonari H, Nakayama R et al. Regulation of Otx2 expression and its functions in mouse forebrain and midbrain. Development 2004: 131: 3319-3331.
29. Gherzi R, Briata P, Boncinelli E et al. The human homeodomain protein OTX2 binds to the human tenascin-C promoter and trans-represses its activity in transfected cells. DNA Cell Biol 1997: 16: 559-567.
30. Morgan R, Hooiveld MH, In der Reiden P et al. A conserved 30 base pair element in the Wnt-5a promoter is sufficient both to drive its'early embryonic expression and to mediate its'repression by otx2. Mech Dev 1999: 85: 97-102.
31. Kelley CG, Lavorgna G, Clark ME et al. The Otx2 homeoprotein regulates expression from the gonadotropin-releasing hormone proximal promoter. Mol Endocrinol 2000: 14: 1246-1256.
32. Spieler D, Baumer N, Stebler J et al. Involvement of Pax6 and Otx2 in the forebrain-specific regulation of the vertebrate homeobox gene ANF/ Hesx1. Dev Biol 2004: 269: 567-579.
33. Kastury K, Druck T, Huebner K et al. Chromosome locations of human EMX and OTX genes. Genomics 1994: 22: 41-45.
34. Ragge NK, Brown AG, Poloschek CM et al. Heterozygous mutations of OTX2 cause severe ocular malformations. Am J Hum Genet 2005: 76: 1008-1022.
35. Simeone A, Gulisano M, Acampora D et al. Two vertebrate homeobox genes related to the Drosophila empty spiracles gene are expressed in the embryonic cerebral cortex. EMBO J 1992: 11: 2541-2550.
36. Pellegrini M, Mansouri A, Simeone A et al. Dentate gyrus formation requires Emx2. Development 1996: 122: 3893-3898.
37. Suda Y, Hossain ZM, Kobayashi C et al. Emx2 directs the development of diencephalon in cooperation with Otx2. Development 2001: 128: 2433-2450.
38. Hamasaki T, Leingartner A, Ringstedt T et al. EMX2 regulates sizes and positioning of the primary sensory and motor areas in neocortex by direct specification of cortical progenitors. Neuron 2004: 43: 359-372.
39. Qiu M, Anderson S, Chen S et al. Mutation of the Emx-1 homeobox gene disrupts the corpus callosum. Dev Biol 1996: 178: 174-178.
40. Hong SM, Liu Z, Fan Y et al. Reduced hippocampal neurogenesis and skill reaching performance in adult Emx1 mutant mice. Exp Neurol 2007: 206: 24-32.
41. Bishop KM, Garel S, Nakagawa Y et al. Emx1 and Emx2 cooperate to regulate cortical size, lamination, neuronal differentiation, development of cortical efferents, and thalamocortical pathfinding. J Comp Neurol 2003: 457: 345-360.
42. Theil T, Alvarez-Bolado G, Walter A et al. Gli3 is required for Emx gene expression during dorsal telencephalon development. Development 1999: 126: 3561-3571.
43. Theil T, Aydin S, Koch S et al. Wnt and Bmp signalling cooperatively regulate graded Emx2 expression in the dorsal telencephalon. Development 2002: 129: 3045-3054.
44. Hallonet M, Hollemann T, Wehr R et al. Vax1 is a novel homeobox-containing gene expressed in the developing anterior ventral forebrain. Development 1998: 125: 2599-2610.
45. Barbieri AM, Lupo G, Bulfone A et al. A homeobox gene, vax2, controls the patterning of the eye dorsoventral axis. Proc Natl Acad Sci U S A 1999: 96: 10729-10734.
46. Hallonet M, Hollemann T, Pieler T et al. Vax1, a novel homeobox-containing gene, directs development of the basal forebrain and visual system. Genes Dev 1999: 13: 3106-3114.
47. Quiring R, Walldorf U, Kloter U et al. Homology of the eyeless gene of Drosophila to the Small eye gene in mice and Aniridia in humans. Science 1994: 265: 785-789.
48. Walther C, Gruss P. Pax-6, a murine paired box gene, is expressed in the developing CNS. Development 1991: 113: 1435-1449.
49. Stoykova A, Gotz M, Gruss P et al. Pax6-dependent regulation of adhesive patterning, R-cadherin expression and boundary formation in developing forebrain. Development 1997: 124: 3765-3777.
50. Toresson H, Potter SS, Campbell K. Genetic control of dorsal-ventral identity in the telencephalon: Opposing roles for Pax6 and Gsh2. Development 2000: 127: 4361-4371.
51. Estivill-Torrus G, Pearson H, van Heyningen V et al. Pax6 is required to regulate the cell cycle and the rate of progression from symmetrical to asymmetrical division in mammalian cortical progenitors. Development 2002: 129: 455-466.
52. Heins N, Malatesta P, Cecconi F et al. Glial cells generate neurons: The role of the transcription factor Pax6. Nat Neurosci 2002: 5: 308-315.
53. Hevner RF, Miyashita-Lin E, Rubenstein JL. Cortical and thalamic axon pathfinding defects in Tbr1, Gbx2, and Pax6 mutant mice: Evidence that cortical and thalamic axons interact and guide each other. J Comp Neurol 2002: 447: 8-17.
54. Muzio L, DiBenedetto B, Stoykova A et al. Conversion of cerebral cortex into basal ganglia in Emx2(-/-) Pax6(Sey/Sey) double-mutant mice. Nat Neurosci 2002: 5: 737-745.
55. Berger J, Berger S, Tuoc TC et al. Conditional activation of Pax6 in the developing cortex of transgenic mice causes progenitor apoptosis. Development 2007: 134: 1311-1322.
56. Kim EA, Noh YT, Ryu MJ et al. Phosphorylation and transactivation of Pax6 by homeodomain-interacting protein kinase 2. J Biol Chem 2006: 281: 7489-7497.
57. Scardigli R, Baumer N, Gruss P et al. Direct and concentration-dependent regulation of the proneural gene Neurogenin2 by Pax6. Development 2003: 130: 3269-3281.
58. Grinchuk O, Kozmik Z, Wu X et al. The Optimedin gene is a downstream target of Pax6. J Biol Chem 2005: 280: 35228-35237.
59. Meech R, Kallunki P, Edelman GM et al. A binding site for homeodomain and Pax proteins is necessary for L1 cell adhesion molecule gene expression by Pax-6 and bone morphogenetic proteins. Proc Natl Acad Sci U S A 1999: 96: 2420-2425.
60. Holm PC, Mader MT, Haubst N et al. Loss- and gain-of-function analyses reveal targets of Pax6 in the developing mouse telencephalon. Mol Cell Neurosci 2007: 34: 99-119.
61. Dansault A, David G, Schwartz C et al. Three new PAX6 mutations including one causing an unusual ophthalmic phenotype associated with neurodevelopmental abnormalities. Mol Vis 2007: 13: 511-523.
62. Sisodiya SM, Free SL, Williamson KA et al. PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans. Nat Genet 2001: 28: 214-216.
63. Ellison-Wright Z, Heyman I, Frampton I et al. Heterozygous PAX6 mutation, adult brain structure and fronto-striato-thalamic function in a human family. Eur J Neurosci 2004: 19: 1505-1512.
64. Tzoulaki I, White IM, Hanson IM. PAX6 mutations: Genotype-phenotype correlations. BMC Genet 2005: 6: 27.
65. Anderson SA, Qiu M, Bulfone A et al. Mutations of the homeobox genes Dlx-1 and Dlx-2 disrupt the striatal subventricular zone and differentiation of late born striatal neurons. Neuron 1997: 19: 27-37.
66. Liu JK, Ghattas I, Liu S et al. Dlx genes encode DNA-binding proteins that are expressed in an overlapping and sequential pattern during basal ganglia differentiation. Dev Dyn 1997: 210: 498-512.
67. Eisenstat DD, Liu JK, Mione M et al. DLX-1, DLX-2, and DLX-5 expression define distinct stages of basal forebrain differentiation. J Comp Neurol 1999: 414: 217-237.
68. Panganiban G, Rubenstein JL. Developmental functions of the Distal-less/ Dlx homeobox genes. Development 2002: 129: 4371-4386.
69. Zhou QP, Le TN, Qiu X et al. Identification of a direct Dlx homeodomain target in the developing mouse forebrain and retina by optimization of chromatin immunoprecipitation. Nucleic Acids Res 2004: 32: 884-892.
70. McGuinness T, Porteus MH, Smiga S et al. Sequence, organization, and transcription of the Dlx-1 and Dlx-2 locus. Genomics 1996: 35: 473-485.
71. Qiu M, Bulfone A, Martinez S et al. Null mutation of Dlx-2 results in abnormal morphogenesis of proximal first and second branchial arch derivatives and abnormal differentiation in the forebrain. Genes Dev 1995: 9: 2523-2538.
72. Anderson SA, Eisenstat DD, Shi L et al. Interneuron migration from basal forebrain to neocortex: Dependence on Dlx genes. Science 1997: 278: 474-476.
73. Marin O, Yaron A, Bagri A et al. Sorting of striatal and cortical interneurons regulated by semaphorin-neuropilin interactions. Science 2001: 293: 872-875.
74. Bulfone A, Wang F, Hevner R et al. An olfactory sensory map develops in the absence of normal projection neurons or GABAergic interneurons. Neuron 1998: 21: 1273-1282.
75. Pleasure SJ, Anderson S, Hevner R et al. Cell migration from the ganglionic eminences is required for the development of hippocampal GABAergic interneurons. Neuron 2000: 28: 727-740.
76. Cobos I, Calcagnotto ME, Vilaythong AJ et al. Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy. Nat Neurosci 2005: 8: 1059-1068.
77. Petryniak MA, Potter GB, Rowitch DH et al. Dlx1 and Dlx2 control neuronal versus oligodendroglial cell fate acquisition in the developing forebrain. Neuron 2007: 55: 417-433.
78. Poitras L, Ghanem N, Hatch G et al. The proneural determinant MASH1 regulates forebrain Dlx1/2 expression through the I12b intergenic enhancer. Development 2007: 134: 1755-1765.
79. Zerucha T, Stuhmer T, Hatch G et al. A highly conserved enhancer in the Dlx5/Dlx6 intergenic region is the site of cross-regulatory interactions between Dlx genes in the embryonic forebrain. J Neurosci 2000: 20: 709-721.
80. Stuhmer T, Puelles L, Ekker M et al. Expression from a Dlx gene enhancer marks adult mouse cortical GABAergic neurons. Cereb Cortex 2002: 12: 75-85.
81. Stuhmer T, Anderson SA, Ekker M et al. Ectopic expression of the Dlx genes induces glutamic acid decarboxylase and Dlx expression. Development 2002: 129: 245-252.
82. Le TN, Du G, Fonseca M et al. Dlx homeobox genes promote cortical interneuron migration from the basal forebrain by direct repression of the semaphorin receptor neuropilin-2. J Biol Chem 2007: 282: 19071-19081.
83. Cobos I, Borello U, Rubenstein JL. Dlx transcription factors promote migration through repression of axon and dendrite growth. Neuron 2007: 54: 873-888.
84. Philippe C, Villard L, De Roux N et al. Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: A molecular update. Eur J Med Genet 2006: 49: 9-18.
85. Horike S, Cai S, Miyano M et al. Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome. Nat Genet 2005: 37: 31-40.
86. Chang Q, Khare G, Dani V et al. The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Neuron 2006: 49: 341-348.
87. de Melo J, Zhou QP, Zhang Q et al. Dlx2 homeobox gene transcriptional regulation of Trkb neurotrophin receptor expression during mouse retinal development. Nucleic Acids Res 2007: 1-13 (published online December 17, 2007).
88. Nirenberg M, Nakayama K, Nakayama N et al. The NK-2 homeobox gene and the early development of the central nervous system of Drosophila. Ann N Y Acad Sci 1995: 758: 224-242.
89. Kimura S, Hara Y, Pineau T et al. The T/ebp null mouse: Thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes Dev 1996: 10: 60-69.
90. Lazzaro D, Price M, de Felice M et al. The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain. Development 1991: 113: 1093-1104.
91. Yun K, Potter S, Rubenstein JL. Gsh2 and Pax6 play complementary roles in dorsoventral patterning of the mammalian telencephalon. Development 2001: 128: 193-205.
92. Sussel L, Marin O, Kimura S 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. Development 1999: 126: 3359-3370.
93. Pabst O, Herbrand H, Takuma N et al. NKX2 gene expression in neuroectoderm but not in mesendodermally derived structures depends on sonic hedgehog in mouse embryos. Dev Genes Evol 2000: 210: 47-50.
94. Vokes SA, Ji H, McCuine S et al. Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning. Development 2007: 134: 1977-1989.
95. Pohlenz J, Dumitrescu A, Zundel D et al. Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice. J Clin Invest 2002: 109: 469-473.
96. Krude H, Schutz B, Biebermann H et al. Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. J Clin Invest 2002: 109: 475-480.
97. Breedveld GJ, van Dongen JW, Danesino C et al. Mutations in TITF-1 are associated with benign hereditary chorea. Hum Mol Genet 2002: 11: 971-979.
98. Provenzano C, Veneziano L, Appleton R et al. Functional characterization of a novel mutation in TITF-1 in a patient with benign hereditary chorea. J Neurol Sci 2008: 264: 56-62.
99. Moya CM, Perez de Nanclares G, Castano L et al. Functional study of a novel single deletion in the TITF1/NKX2.1 homeobox gene that produces congenital hypothyroidism and benign chorea but not pulmonary distress. J Clin Endocrinol Metab 2006: 91: 1832-1841.
100. Minoo P, Hu L, Xing Y et al. Physical and functional interactions between homeodomain NKX2.1 and winged helix/forkhead FOXA1 in lung epithelial cells. Mol Cell Biol 2007: 27: 2155-2165.
101. Minoo P, Hu L, Zhu N et al. SMAD3 prevents binding of NKX2.1 and FOXA1 to the SpB promoter through its MH1 and MH2 domains. Nucleic Acids Res 2008: 36: 179-188.
102. Lonigro R, Donnini D, Zappia E et al. Nestin is a neuroepithelial target gene of thyroid transcription factor-1, a homeoprotein required for forebrain organogenesis. J Biol Chem 2001: 276: 47807-47813.
103. Pelizzoli R, Tacchetti C, Luzzi P et al. TTF-1/NKX2.1 up-regulates the in vivo transcription of nestin. Int J Dev Biol 2008: 52: 55-62.
104. Singh G, Kaur S, Stock JL et al. Identification of 10 murine homeobox genes. Proc Natl Acad Sci U S A 1991: 88: 10706-10710.
105. Weiss JB, Von Ohlen T, Mellerick DM et al. Dorsoventral patterning in the Drosophila central nervous system: The intermediate neuroblasts defective homeobox gene specifies intermediate column identity. Genes Dev 1998: 12: 3591-3602.
106. Von Ohlen T, Syu LJ, Mellerick DM. Conserved properties of the Drosophila homeodomain protein, Ind. Mech Dev 2007: 124: 925-934.
107. Szucsik JC, Witte DP, Li H et al. Altered forebrain and hindbrain development in mice mutant for the Gsh-2 homeobox gene. Dev Biol 1997: 191: 230-242.
108. Gregg C, Weiss S. CNTF/LIF/gp130 receptor complex signaling maintains a VZ precursor differentiation gradient in the developing ventral forebrain. Development 2005: 132: 565-578.
109. Corbin JG, Gaiano N, Machold RP et al. The Gsh2 homeodomain gene controls multiple aspects of telencephalic development. Development 2000: 127: 5007-5020.
110. Mizuguchi R, Kriks S, Cordes R et al. Ascl1 and Gsh1/2 control inhibitory and excitatory cell fate in spinal sensory interneurons. Nat Neurosci 2006: 9: 770-778.
111. Waclaw RR, Wang B, Campbell K. The homeobox gene Gsh2 is required for retinoid production in the embryonic mouse telencephalon. Development 2004: 131: 4013-4020.
112. Schneitz K, Spielmann P, Noll M. Molecular genetics of aristaless, a prd-type homeo box gene involved in the morphogenesis of proximal and distal pattern elements in a subset of appendages in Drosophila. Genes Dev 1993: 7: 114-129.
113. Miura H, Yanazawa M, Kato K et al. Expression of a novel aristaless related homeobox gene 'Arx'in the vertebrate telencephalon, diencephalon and floor plate. Mech Dev 1997: 65: 99-109.
114. Stromme P, Mangelsdorf ME, Shaw MA et al. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nat Genet 2002: 30: 441-445.
115. Bienvenu T, Poirier K, Friocourt G et al. ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. Hum Mol Genet 2002: 11: 981-991.
116. Sherr EH. The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): One gene leads to many phenotypes. Curr Opin Pediatr 2003: 15: 567-571.
117. Gecz J, Cloosterman D, Partington M. ARX: A gene for all seasons. Curr Opin Genet Dev 2006: 16: 308-316.
118. Kitamura K, Yanazawa M, Sugiyama N et al. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet 2002: 32: 359-369.
119. Cobos I, Broccoli V, Rubenstein JL. The vertebrate ortholog of Aristaless is regulated by Dlx genes in the developing forebrain. J Comp Neurol 2005: 483: 292-303.
120. Melkman T, Sengupta P. Regulation of chemosensory and GABAergic motor neuron development by the C. elegans Aristaless/Arx homolog alr-1. Development 2005: 132: 1935-1949.
121. Seufert DW, Prescott NL, El-Hodiri HM. Xenopus aristaless-related homeobox (xARX) gene product functions as both a transcriptional activator and repressor in forebrain development. Dev Dyn 2005: 232: 313-324.
122. McKenzie O, Ponte I, Mangelsdorf M et al. Aristaless-related homeobox gene, the gene responsible for West syndrome and related disorders, is a Groucho/transducin-like enhancer of split dependent transcriptional repressor. Neuroscience 2007: 146: 236-247.
123. Collombat P, Hecksher-Sorensen J, Broccoli V et al. The simultaneous loss of Arx and Pax4 genes promotes a somatostatin-producing cell fate specification at the expense of the alpha- and beta-cell lineages in the mouse endocrine pancreas. Development 2005: 132: 2969-2980.
124. Freyd G, Kim SK, Horvitz HR. Novel cysteine-rich motif and homeodomain in the product of the Caenorhabditis elegans cell lineage gene lin-11. Nature 1990: 344: 876-879.
125. Hunter CS, Rhodes SJ. LIM-homeodomain genes in mammalian development and human disease. Mol Biol Rep 2005: 32: 67-77.
126. Shawlot W, Behringer RR. Requirement for Lim1 in head-organizer function. Nature 1995: 374: 425-430.
127. Xu Y, Baldassare M, Fisher P et al. LH-2: A LIM/homeodomain gene expressed in developing lymphocytes and neural cells. Proc Natl Acad Sci U S A 1993: 90: 227-231.
128. O'Keefe DD, Thor S, Thomas JB. Function and specificity of LIM domains in Drosophila nervous system and wing development. Development 1998: 125: 3915-3923.
129. Porter FD, Drago J, Xu Y et al. Lhx2, a LIM homeobox gene, is required for eye, forebrain, and definitive erythrocyte development. Development 1997: 124: 2935-2944.
130. Kolterud A, Alenius M, Carlsson L et al. The Lim homeobox gene Lhx2 is required for olfactory sensory neuron identity. Development 2004: 131: 5319-5326.
131. Remedios R, Subramanian L, Tole S. LIM genes parcellate the embryonic amygdala and regulate its development. J Neurosci 2004: 24: 6986-6990.
132. Toyama R, Curtiss PE, Otani H et al. The LIM class homeobox gene lim5: implied role in CNS patterning in Xenopus and zebrafish. Dev Biol 1995: 170: 583-593.
133. Zhao Y, Sheng HZ, Amini R et al. Control of hippocampal morphogenesis and neuronal differentiation by the LIM homeobox gene Lhx5. Science 1999: 284: 1155-1158.
134. Peng G, Westerfield M. Lhx5 promotes forebrain development and activates transcription of secreted Wnt antagonists. Development 2006: 133: 3191-3200.
135. Pillai A, Mansouri A, Behringer R et al. Lhx1 and Lhx5 maintain the inhibitory-neurotransmitter status of interneurons in the dorsal spinal cord. Development 2007: 134: 357-366.
136. Grigoriou M, Tucker AS, Sharpe PT et al. Expression and regulation of Lhx6 and Lhx7, a novel subfamily of LIM homeodomain encoding genes, suggests a role in mammalian head development. Development 1998: 125: 2063-2074.
137. Lavdas AA, Grigoriou M, Pachnis V et al. The medial ganglionic eminence gives rise to a population of early neurons in the developing cerebral cortex. J Neurosci 1999: 19: 7881-7888.
138. Gong S, Zheng C, Doughty ML et al. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 2003: 425: 917-925.
139. Liodis P, Denaxa M, Grigoriou M et al. Lhx6 activity is required for the normal migration and specification of cortical interneuron subtypes. J Neurosci 2007: 27: 3078-3089.
140. Choi GB, Dong HW, Murphy AJ et al. Lhx6 delineates a pathway mediating innate reproductive behaviors from the amygdala to the hypothalamus. Neuron 2005: 46: 647-660.
141. Asbreuk CH, van Schaick HS, Cox JJ et al. The homeobox genes Lhx7 and Gbx1 are expressed in the basal forebrain cholinergic system. Neuroscience 2002: 109: 287-298.
142. Zhao Y, Marin O, Hermesz E et al. The LIM-homeobox gene Lhx8 is required for the development of many cholinergic neurons in the mouse forebrain. Proc Natl Acad Sci U S A 2003: 100: 9005-9010.
143. Bachy I, Retaux S. GABAergic specification in the basal forebrain is controlled by the LIM-hd factor Lhx7. Dev Biol 2006: 291: 218-226.
144. Agulnick AD, Taira M, Breen JJ et al. Interactions of the LIM-domain-binding factor Ldb1 with LIM homeodomain proteins. Nature 1996: 384: 270-272.
145. Bach I, Rodriguez-Esteban C, Carriere C et al. RLIM inhibits functional activity of LIM homeodomain transcription factors via recruitment of the histone deacetylase complex. Nat Genet 1999: 22: 394-399.
146. Ostendorff HP, Peirano RI, Peters MA et al. Ubiquitination-dependent cofactor exchange on LIM homeodomain transcription factors. Nature 2002: 416: 99-103.