Otx1 function overlaps with Otx2 in development of mouse forebrain and midbrain

Suda, Yoko; Matsuo, Isao; Kuratani, Shigeru; Aizawa, Shinichi

doi:10.1046/j.1365-2443.1996.900288.x

Cited by 56 publications

(35 citation statements)

References 40 publications

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“…This suggests that Otx1 and Otx2 play synergistic roles in the development of several brain structures. It is worth noting the strong phenotypic variability of the double heterozogotes, in spite of the fact that the genetic background is strictly the same [48]. This is consistent with observations in humans.…”

Section: Interactions Between Loci: Non-allelic Non-complementationsupporting

confidence: 87%

Dominance and gene dosage balance in health and disease: why levels matter!

Veitia

Birchler

2009

The Journal of Pathology

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The classical concept of genetic dominance is a simplification of a more quantitative reality. This is clearly exemplified by aneuploid syndromes, of which the best known case is trisomy 21. Moreover, there is an increasing number of clinical conditions due to reduced dosage (haploinsufficiency) of genes encoding transcription factors and other proteins involved in signal transduction and macromolecular complexes. In such genetic diseases, a high degree of phenotypic variability is observed, which calls for an explanation. The sources of dominance are heterogeneous and difficult to cover in a brief review. Here, we will focus on the molecular bases of dosage-sensitive syndromes from the perspective of the gene dosage balance hypothesis, which postulates that stoichiometric alterations of macromolecular complexes or cellular networks are responsible for dominant phenotypes, because of the existing non-linear relationships between the genotypic and phenotypic values with which they are associated.

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Section: Interactions Between Loci: Non-allelic Non-complementationsupporting

confidence: 87%

Dominance and gene dosage balance in health and disease: why levels matter!

Veitia

Birchler

2009

The Journal of Pathology

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“…Furthermore, Otx1 +/-Otx2 +/-mutants are postnatally lethal, and Otx1 -/-Otx2 +/-phenotype could also not be examined. Otx1 -/-mutants do not exhibit marked defects in forebrain or midbrain development (Suda et al, 1996). These situations obscured the onset and the extent of cooperation between Otx1 and Otx2 in rostral brain development.…”

Section: Introductionmentioning

confidence: 99%

“…The results of analyses of Otx1 +/-Otx2 +/-mutants suggested that Otx2 and Otx1 cooperate in the regionalization of the rostral brain (Acampora et al, 1997;Suda et al, 1996;Suda et al, 2001). Owing to the occurrence of earlier visceral defects in Otx2 -/-mutants, however, this cooperation could not be examined in the Otx2 homozygous mutant state.…”

Section: Introductionmentioning

confidence: 99%

Regulation ofOtx2expression and its functions in mouse forebrain and midbrain

Kurokawa¹,

et al. 2004

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Otx2 expression in the forebrain and midbrain was found to be regulated by two distinct enhancers (FM and FM2) located at 75 kb 5′upstream and 115 kb 3′ downstream. The activities of these two enhancers were absent in anterior neuroectoderm earlier than E8.0; however, at E9.5 their regions of activity spanned the entire mesencephalon and diencephalon with their caudal limits at the boundary with the metencephalon or isthmus. In telencephalon, activities were found only in the dorsomedial aspect. Potential binding sites of OTX and TCF were essential to FM activity, and TCF sites were also essential to FM2 activity. The FM2 enhancer appears to be unique to rodent; however, the FM enhancer region is deeply conserved in gnathostomes. Studies of mutants lacking FM or FM2 enhancer demonstrated that these enhancers indeed regulate Otx2 expression in forebrain and midbrain. Development of mesencephalic and diencephalic regions was differentially regulated in a dose-dependent manner by the cooperation between Otx1and Otx2 under FM and FM2 enhancers: the more caudal the structure the higher the OTX dose requirement. At E10.5 Otx1–/–Otx2ΔFM/ΔFMmutants, in which Otx2 expression under the FM2 enhancer remained,exhibited almost complete loss of the entire diencephalon and mesencephalon;the telencephalon did, however, develop.

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“…Proper regulation and function of this gene is crucial, as the mutation of Otx2 leads to defects in the rostral head in several developmental processes (Acampora et al, 1995;Acampora et al, 1997;Matsuo et al, 1995;Ang et al, 1996;Suda et al, 1996;Suda et al, 1997;Suda et al, 2001;Tian et al, 2002;Hide et al, 2002). However, very little is known about how Otx2 gene expression is dynamically regulated.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the pufferfishOtx2cis-regulators reveals evolutionarily conserved genetic mechanisms for vertebrate head specification

Kimura-Yoshida¹,

Kitajima²,

Oda-Ishii³

et al. 2004

Development

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The Otx2 gene, containing a highly conserved paired-type homeobox, plays a pivotal role in the development of the rostral head throughout vertebrates. Precise regulation of the temporal and spatial expression of Otx2 is likely to be crucial for proper head specification. However, regulatory mechanisms of Otx2 expression remain largely unknown. In this study, the Otx2 genome of the puffer fish Fugu rubripes, which has been proposed as a model vertebrate owing to its highly compact genome, was cloned. Consistently, Fugu Otx2 possesses introns threefold smaller in size than those of the mouse Otx2 gene. Otx2 mRNA was transcribed after MBT, and expressed in the rostral head region throughout the segmentation and pharyngula periods of wild-type Fugu embryos. To elucidate regulatory mechanisms of Otx2 expression, the expression of Otx2-lacZreporter genes nearly covering the Fugu Otx2 locus, from –30.5 to +38.5 kb, was analyzed, by generating transgenic mice. Subsequently, seven independent cis-regulators were identified over an expanse of 60 kb; these regulators are involved in the mediation of spatiotemporally distinct subdomains of Otx2 expression. Additionally, these expression domains appear to coincide with local signaling centers and developing sense organs. Interestingly, most domains do not overlap with one another, which implies that cis-regulators for redundant expression may be abolished exclusively in the pufferfish so as to reduce its genome size. Moreover, these cis-regions were also able to direct expression in zebrafish embryos equivalent to that observed in transgenic mice. Further comparative sequence analysis of mouse and pufferfish intergenic regions revealed eight highly conserved elements within these cis-regulators. Therefore, we propose that, in vertebrate evolution, the Otx2 promoter acquires multiple, spatiotemporally specific cis-regulators in order to precisely control highly coordinated processes in head development.

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Otx1 function overlaps with Otx2 in development of mouse forebrain and midbrain

Cited by 56 publications

References 40 publications

Dominance and gene dosage balance in health and disease: why levels matter!

Dominance and gene dosage balance in health and disease: why levels matter!

Regulation ofOtx2expression and its functions in mouse forebrain and midbrain

Characterization of the pufferfishOtx2cis-regulators reveals evolutionarily conserved genetic mechanisms for vertebrate head specification

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