Epilepsy and brain abnormalities in mice lacking the Otx1 gene

Acampora, Dario; Mazan, Sylvie; Avantaggiato, Virginia; Barone, Paolo; Tuorto, Francesca; Lallemand, Yvan; Brûlet, Philippe; Simeone, Antonio

doi:10.1038/ng1096-218

Cited by 282 publications

(183 citation statements)

References 20 publications

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“…Animals heterozygous for a loss-of-function mutation of otx2 show abnormalities in the anterior portion of the embryo, including dislocation of the retina and the loss of the lens (50). This eye phenotype, however, is likely to be a secondary effect, resulting from a deformity of the entire rostral region, as the homozygous otx2 mutants exhibit loss of both the fore-and midbrain (50)(51)(52). six3, a murine homolog of the sine oculis gene in Drosophila, is reported to be specifically expressed in the most anterior ridge region of the forebrain (22), which will give rise to derivatives of the nonneural ectoderm.…”

Section: Discussionmentioning

confidence: 99%

rax , a novel paired-type homeobox gene, shows expression in the anterior neural fold and developing retina

Furukawa

Kozak

Cepko

1997

Proc. Natl. Acad. Sci. U.S.A.

338

289

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Development of the vertebrate eye has been found to require the activity of several genes encoding homeodomain proteins (Freund, C., Horsford, D. J. & McInnes, R. R. (1996) Hum. Mol. Genet. 5, 1471-1488). Some of these genes, or portions thereof, are highly conserved across phyla. In this paper, we report the identification of a novel homeobox gene, rax (retina and anterior neural fold homeobox), whose expression pattern suggests an important role in eye development. The predicted amino acid sequence of Rax comprises a protein with a paired-type homeobox, as well as the octapeptide that is found in many paired-type homeobox genes. In addition, in the C terminus of Rax, we found a 15-aa domain that we have named the OAR domain. This domain is also found in several other homeobox genes. In the early mouse embryo, rax is expressed in the anterior neural fold, including areas that will give rise to the ventral forebrain and optic vesicles. Once the optic vesicles form, rax expression is restricted to the ventral diencephalon and the optic vesicles. At later stages, rax expression is found only in the developing retina. After birth, the expression of rax is restricted to the zone of proliferating cells within the retina, and expression gradually decreases as proliferation declines. These findings suggest that rax is one of the molecules that define the eye field during early development and that it has a role in the proliferation and͞or differentiation of retinal cells.During vertebrate development, the central nervous system emerges as a highly complex, patterned structure with an enormous diversity of neuronal and glial cell types. The vertebrate retina is a relatively well described and accessible structure that provides an excellent model system for studies of patterning and cell fate determination within the central nervous system (1). In the early stages of eye development, the optic vesicles evaginate from the ventral forebrain, making contact with the overlying surface ectoderm at embryonic day 9 (E9) in the mouse. Subsequently, the optic vesicle invaginates to form the optic cup, while overlying surface ectoderm gives rise to the lens placode (2, 3). Retinal neurogenesis then proceeds within the inner layer of the optic cup. The mitotic progenitors within the optic cup line the surface apposed to the former lumen of the neural tube, in an area known as the ventricular zone (VZ). Postmitotic progeny of the retina migrate away from the VZ as they differentiate to form the laminar structure of the mature retina. While the different retinal cells are born in a sequence conserved among many species, more than one cell type is born at any one time (4). Lineage analyses in several species have shown that retinal progenitors remain multipotent throughout development (5-8).

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Section: Discussionmentioning

confidence: 99%

rax , a novel paired-type homeobox gene, shows expression in the anterior neural fold and developing retina

Furukawa

Kozak

Cepko

1997

Proc. Natl. Acad. Sci. U.S.A.

338

289

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“…Anatomic studies have revealed that some mouse mutants, such as Otx1 (Acampora et al 1996), Ecl (Cryns et al 2004), Whl (Alavizadeh et al 2001), Obt, Todo, Dz, Cyn, Edy, Mt, and Lda (Kiernan et al 2002), and Crsl and Whi (Hawker et al 2005), show gross changes in the bony semicircular canals. In contrast, others, such as stargazer (Khan et al 2004), het (Paffenholz et al 2004), isk (Vetter et al 1996), tlt and mlh (Hurle et al 2003), Pmca2 (Kozel et al 1998), shaker/waltzer (Sun 2001), and hscy (Longo-Guess et al 2005), have not been reported as having significant bony abnormalities.…”

Section: Introductionmentioning

confidence: 99%

Planar Relationships of the Semicircular Canals in Two Strains of Mice

Calabrese

Hullar

2006

JARO

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The mouse is increasingly important as a subject of vestibular research. Although many studies have focused on the vestibular responses of mice to angular rotation, the geometry of their semicircular canals has not been described. High-voltage X-ray computed tomography was used to measure the anatomy of the semicircular canals of two strains of mice, C57Bl/6J and CBA/CaJ. The horizontal plane of a stereotaxic coordinate system was defined by the midpoints of the external auditory meati and the point where the incisors emerge from the maxilla. The centroids of the lumens of the bony canals were calculated, and planes that describe the canals were fit using a least-squares regression analysis to the resulting points. Vectors normal to each regressed plane were used to represent the corresponding canal's axis of rotation, and angles of these vectors relative to skull landmarks as well as to each other were calculated. The horizontal canal of the mouse was found to be angled anteriorly upward 17.8-for CBA/CaJ and 32.6-for C57Bl/6J from the reference horizontal plane. Angles between ipsilateral canals deviated up to 12.3-from orthogonal, and angles between contralateral synergistic canals (left anterior-right posterior, right anterior-left posterior, and horizontal-horizontal) deviated from parallel by up to 14.8-. The orientations of the canals within the head as well as the orientations of the canals relative to each other were significantly different between the two strains, suggesting that care must be taken in the design and interpretation of developmental and physiologic studies involving different mouse strains.

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“…For example, Dlx5, which is expressed in the dorsal side of the otic vesicle, is required for the formation of the semicircular canals (Acampora et al, 1999;Depew et al, 1999). Otx1, which is expressed in the ventral side, is needed for the correct morphogenesis of the cochlea (Acampora et al, 1996). The establishment of such a gene expression profile in the otic vesicle, orchestrated by networks or cascades of transcription factors, is essential for inner ear development.…”

Section: Establishment Of Otic Vesicle Patterning By Six1mentioning

confidence: 99%

Six1controls patterning of the mouse otic vesicle

et al. 2004

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A similar gene network was found to control chick myogenesis, in which Six1, Eya2 and Dach2 synergistically regulate the expression of myogenic genes such as myogenin and MyoD (Heanue et Six1 is a member of the Six family homeobox genes, which function as components of the Pax-Six-Eya-Dach gene network to control organ development. Six1 is expressed in otic vesicles, nasal epithelia, branchial arches/pouches, nephrogenic cords, somites and a limited set of ganglia. In this study, we established Six1-deficient mice and found that development of the inner ear, nose, thymus, kidney and skeletal muscle was severely affected. Six1-deficient embryos were devoid of inner ear structures, including cochlea and vestibule, while their endolymphatic sac was enlarged. The inner ear anomaly began at around E10.5 and Six1 was expressed in the ventral region of the otic vesicle in the wild-type embryos at this stage. In the otic vesicle of Six1-deficient embryos, expressions of Otx1, Otx2, Lfng and Fgf3, which were expressed ventrally in the wildtype otic vesicles, were abolished, while the expression domains of Dlx5, Hmx3, Dach1 and Dach2, which were expressed dorsally in the wild-type otic vesicles, expanded ventrally. Our results indicate that Six1 functions as a key regulator of otic vesicle patterning at early embryogenesis and controls the expression domains of downstream otic genes responsible for respective inner ear structures. In addition, cell proliferation was reduced and apoptotic cell death was enhanced in the ventral region of the otic vesicle, suggesting the involvement of Six1 in cell proliferation and survival. In spite of the similarity of otic phenotypes of Six1-and Shh-deficient mice, expressions of Six1 and Shh were mutually independent.

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Epilepsy and brain abnormalities in mice lacking the Otx1 gene

Cited by 282 publications

References 20 publications

rax , a novel paired-type homeobox gene, shows expression in the anterior neural fold and developing retina

rax , a novel paired-type homeobox gene, shows expression in the anterior neural fold and developing retina

Planar Relationships of the Semicircular Canals in Two Strains of Mice

Six1controls patterning of the mouse otic vesicle

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