Homeobox genes and disease

Current Opinion in Genetics and Development

Volumn 7, Issue 3, 1997, Pages 331-337

  Boncinelli, Edoardo ^a,b  

^a SAN RAFFAELE HOSPITAL   (Italy)

^b CNR   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

CONGENITAL DISORDER; DEVELOPMENTAL GENETICS; GENE MUTATION; HOMEOBOX; HUMAN; MAMMAL; MULTIGENE FAMILY; NONHUMAN; PRIORITY JOURNAL; REVIEW; SOMATIC CELL GENETICS;

MAMMALIA;

EID: 0030879040     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-437X(97)80146-3     Document Type: Article

References (67)

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4. Chayelin L, Volovitch M, Joliot AH, Perez F, Prochiantz A: Transcription factor Hoxa-5 is taken up by cells in culture and conveyed to their nuclei. Mech Dev 1996, 55:111-117.
5. Briata P, Di Blas E, Gulisano M, Mallamaci A, Iannone R, Boncinelli E, Corte G: EMX1 homeoprotein is expressed in cell nuclei of the developing cerebral cortex and in axons of the olfactory sensory neurons. Mech Dev 1996, 57:169-180. The EMX1 homeoprotein was found to be localized in cell nuclei of some regions of the developing brain, including the developing cerebral cortex. These localizations are in perfect agreement with data from in situ hybridization studies. This homeoprotein, though, was also found in an unexpected localization - the axons of the olfactory nerve, including its synaptic terminals located within the prosencephalic olfactory bulb.
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15. Dollé P, Dierich A, LeLeur M, Schimmang T, Schubaur B, Chambon P, Duboule D: Disruption of the Hoxd-13 gene induces localized heterochrony leading to mice with neotenic limbs. Cell 1993, 75:431-441.
16. Zakany J, Duboule D: Synpolydactyly in mice with targeted deficiency in the HoxD complex. Nature 1996, 384:69-71. Transgenic mice lacking Hoxd13, Hoxd12 and Hoxd11 genes were simultaneously produced and analyzed. Homozygotes for this deficiency show a synpolydactyly phenotype similar to that observed in humans and associated with a specific HOXD13 protein alteration [13••,14•]. The authors hypothesize the existence of a functional hierarchy among these genes and suggest that these mice might represent a reliable animal model to study human digit malformations.
17. Van der Hoeven F, Zakany J, Duboule D: Gene transpositions in the HoxD complex reveal a hierarchy of regulatory controls. Cell 1996, 85:1025-1035. Hoxd9 and Hoxd11 have been transposed, using a state of the art methodology, to an ectopic position at the 5′ extremity of the HoxD cluster, upstream from Hoxd13. The expression of both transgenes appears to be reprogrammed upon relocation, acquiring part of the characteristics typical of the nearby Hoxd13. These gene transpositions also result in some mis-regulation and cause severe developmental defects. The authors conclude that the functionality of cis-acting regulatory elements present within any single Hox locus primarily depends upon higher-order mechanisms operating throughout the locus.
18. Nakamura T, Largaespada DA, Lee MP, Johnson LA, Ohyashiki K, Toyama K, Chen SJ, Willman CL, Chen IM, Feinberg AP et al:. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nat Genet 1996, 12:154-158. See annotation [19•].
19. Borrow J, Shearman AM, Stanton VP Jr, Becher R, Collins T, Williams AJ, Dubé I, Katk F, Kwong YL, Morris C: The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9. Nat Genet 1996, 12:159-167. These two papers [18•,19•] report the molecular analysis of the breakpont region of the translocation t(7;11) associated with a human acute myeloid leukaemia. These findings, taken together with evidence emerging from the following paper [20], suggest a probable involvement of many other homeobox genes in neoplastic disorders of blood cell differentiation. Even if present data are not sufficient to explain the aetiology of this leukaemia at the molecular level, it is interesting to note that HOXA9 expression is associated with terminal differentiation along the myelomonocytic cell lineage [66].
20. Nakamura T, Largaespada DA, Shauhnessy JD Jr, Jenkins NA, Copeland NG: Cooperative activation of Hoxa and Pbx1-related genes in murine myeloid leukemias. Nat Genet 1996, 12:149-153.
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23. Fromental-Ramain C, Warot X, Messadecq N, LeMeur M, Dollé P, Chambon P: Hoxa-13 and Hoxd-13 play a crucial role in the patterning of the limb autopod. Development 1996, 122:2997-3011.
24. Favier B, Rijli FM, Fromental-Ramain C, Fraulob V, Chambon P, Dollé P: Functional cooperation between the non-paralogous genes Hoxa-10 and Hoxd-11 in the developing forelimb and axial skeleton. Development 1996, 122:449-460.
25. Benson GV, Lim H, Paria BC, Satokata I, Dey SK, Maas RL: Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeosis and loss of maternal Hoxa-10 expression. Development 1996, 122:2687-2696.
26. Fromental-Ramain C, Warot X, Lakkaraju S, Favier B, Haack H, Birling C, Dierich A, Dollé P, Chambon P: Specific and redundant functions of the paralogous Hoxa-9 and Hoxd-9 genes in forelimb and axial skeleton patterning. Development 1996, 122:461-472.
27. Studer M, Lumsden A, Ariza-McNaughton L, Bradley A, Krumlauf R: Altered segmental identity and abnormal migration of motor neurons in mice lacking Hoxb-1. Nature 1996, 384:630-634. See annotation [28•].
28. Goddard JM, Rossel M, Manley NR, Capecchi MR: Mice with targeted disruption of Hoxb-1 fail to form the motor nucleus of the VIIth nerve. Development 1996, 122:3217-3228. These two papers [27•,28•] report the analysis of mice lacking Hoxb1, a 3′ Hox gene predominantly expressed in rhombomere r4. In both papers, the analysis focuses on the development of motor neurons in r4, which is not deleted as is the case for mice lacking the homologous Hoxa1. Analysis with retrograde labelling and motor neuron markers show that facial neurons and peripheral projections are initially formed in mutant r4; however, the neurons exhibit altered migratory behaviours, ultimately resulting in the loss of the motor nucleus of the facial (VII cranial) nerve. The resemblance of this phenotype with a few human defects is also suggested [28•].
29. Alexandre D, Clarke JDW, Oxtoby E, Yan Y-L, Jowett T, Holder N: Ectopic expression of Hoxa-1 in the zebrafish alters the fate of the mandibular arch neural crest and phenocopies a retinoic acid-induced phenotype. Development 1996, 122:735-746.
30. Saldivar JR, Krull CE, Krumlauf R, Ariza-McNaughton L, Bronner-Fraser M: Rhombomere of origin determines autonomous versus environmentally regulated expression of Hoxa3 in the avian embryo. Development 1996, 122:895-904.
31. Itasaki N, Sharpe J, Morrison A, Krumlauf R: Reprogramming Hox expression in the vertebrate hindbrain: influence of paraxial mesoderm and rhombomere transposition. Neuron 1996, 16:487-500. Using chick-chick and chick-transgenic mouse graftings, the authors analyze the establishment and maintenance of Hox gene expression involved in specifying rhombomere identities. In particular, anterior-to-posterior rhombomere transpositions result in a progressive posterior transformation and coordinate induction of new Hox gene expression. The nature of these changes depends on both the new antero-posterior position of the graft and its origin. Transposed somites have a graded ability to reprogram Hox gene expression, suggesting that paraxial mesoderm is a source of local positional information.
32. Wingate RJT, Lumsden A: Persistence of rhombomeric organisation in the postsegmental hindbrain. Development 1996, 122:2143-2152.
33. Bally-Cuif L, Boncinelli E: Transcription factors and head formation in vertebrates. Bioessays 1997, 19:127-135.
34. Simeone A, Acampora D, Gulisano M, Stornaiuolo A, Boncinelli E: Nested expression domains of four homeobox genes in developing rostral brain. Nature 1992, 358:687-690.
35. Boncinelli E, Mallamaci A: Homeobox genes in vertebrate gastrulation. Curr Opin Genet Dev 1995, 5:619-627.
36. Pannese M, Polo C, Andreazzoli M, Vignali R, Kablar B, Barsacchi G, Boncinelli E: The Xenopus homologue of Otx2 is a maternal homeobox gene that demarcates and specifies anterior body regions. Development 1995, 121:707-720.
37. -/- mutants due to a defective anterior neuroectoderm specification during gastrulation. Development 1995, 121:3279-3290. See annotation [39•].
38. Matsuo I, Kuratani S, Kimura C, Takeda N, Aizawa S: Mouse Otx2 functions in the formation and patterning of rostral head. Genes Dev 1995, 9:2646-2658. See annotation [39•].
39. Ang SL, Jin O, Rhinn M, Daigle N, Stevenson L, Rossant J: A targeted mouse Otx2 mutation leads to severe defects in gastrulation and formation of axial mesoderm and to deletion of rostral brain. Development 1996, 122:243-252. These three papers [37•-39•] report the analysis of mice homozygous and heterozygous for targeted Otx2 null mutations. Homozygous embryos fail to complete gastrulation and stop developing at early midgestation, around day 8-9 post fertilization. These embryos are headless and lack any rostral brain structure anterior to rhombomere r3 in the presumptive hindbrain. The deletion of the anterior neural structures is most likely a consequence of the defective formation of anterior axial mesoderm as these embryos fail to form a recognizable node, head process and prechordal mesoderm during early stages of gastrulation. More posterior structures, however, appear unaffected and a node is recognizable somewhat later, suggesting that normal gastrulation resumes after the stages of anterior axial mesoderm formation. The phenotype of heterozygous Otx2 mutant mice strongly depends on the laboratory strain used. In fact, whereas heterozygotes of some strains do not show any phenotypic alteration, heterozygotes of a particular strain show interesting cephalic phenotypes.
40. Shawlot W, Behringer RR: Requirement for Lim1 in head-organizer function. Nature 1995, 374:425-430. Lim1 is a LIM-class homeobox gene expressed in the organizer region of mouse embryos. Embryos homozygous for a targeted deletion of Lim1 lack anterior head structures whereas the remaining body axis develops normally. A partial secondary axis develops anteriorly in some mutant embryos. Close inspection of the mutant phenotype suggests that what is perturbed is the formation and/or the normal patterning of the early involuting axial mesodermal structures. Analysis of molecular markers reveals that the early phases of gastrulation but, surprisingly, not the late ones, are affected.
41. Acampora D, Mazan S, Avantaggiato V, Barone P, Tuorto F, Lallemand Y, Brulet P, Simeone A: Epilepsy and brain abnormalities in mice lacking the Otx1 gene. Nat Genet 1996, 14:218-222. Otx1 null mice are produced and analyzed. They exhibit spontaneous epileptic behavior with both focal and generalized seizures and multiple abnormalities in forebrain, midbrain and cerebellum. The cerebral cortex is generally reduced, especially in the temporal and perirhinal areas and in the hippocampus. Conversely, the mesencephalon is increased in volume and new lobules occasionally appear in the cerebellum. Development of eyes and ears is also affected. Similar but not identical data are reported in [42].
42. Suda Y, Matsuo I, Kuratani S, Aizawa S: Otx1 function overlaps with Otx2 in development of mouse forebrain and midbrain. Genes to Cells 1996, 1:1031-1034.
43. Noebles JL: Targeting epilepsy genes. Neuron 1996, 16:241-244.
44. Gulisano M, Broccoli V, Pardini C, Boncinelli E: Emx1 and Emx2 show different patterns of expression during proliferation and differentiation of the developing cerebral cortex. Eur J Neurosci 1996, 8:1037-1050.
45. Pellegrini M, Mansouri A, Simeone A, Boncinelli E, Gruss P: Dentate gyrus formation requires Emx2. Development 1996, 122:3893-3898. See annotation [46•].
46. Yoshida M, Suda Y, Matsuo I, Miyamoto N, Takeda N, Kuratani S, Aizawa S: Emx1 and Emx2 functions in development of dorsal telencephalon. Development 1997, 124:101-111. These papers [45•,46•] report the phenotypic analyis of transgenic mice lacking Emx2. The cerebral cortex is generally reduced in these mice - both in extension and in thickness - and the dentate gyrus is missing. The dentate gyrus is known to play a major role in declarative memory and a general one in consolidation of long-term memory. Concomitant with cortical reduction, an expansion of the diencephalic roof is observed. Mice lacking Emx1 are also analyzed in this paper and [47].
47. Qiu M, Anderson S, Chen S, Meneses JJ, Hevner R, Kuwana E, Pedersen RA, Rubenstein JLR: Mutation of the Emx-1 homeobox gene disrupts the corpus callosum. Dev Biol 1996, 178:174-178.
48. Brunelli S, Faiella A, Capra V, Nigro V, Simeone A, Cama A, Boncinelli E: Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly. Nat Genet 1996, 12:94-96. De novo mutations of various types are detected in one copy of EMX2 in sporadic cases of patients affected by schizencephaly. These data are in good agreement with previous hypotheses on the role of this gene in controlling cell proliferation (and, indirectly, cell migration) of cortical neurons. On the other hand, the biological significance of some of the mutations reported in this paper and in [49] is far from clear and further analysis is required. In fact, whereas mutations of clear biological significance such as frameshift mutations or others resulting in disturbances of the splicing pattern of this gene have been reported for patients showing severe forms of schizencephaly, in patients showing milder defects, some mutations have been found which are more difficult to associate with a clear pathological effect. These include putative synonymous mutations and microdeletions within introns.
49. Granata T, Farina L, Faiella A, Cardini R, D'Incerti L, Boncinelli E, Battaglia G: Familial schizencephaly associated with EMX2 mutation. Neurology 1997, in press
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