Pitx2, a Bicoid-Type Homeobox Gene, Is Involved in a Lefty-Signaling Pathway in Determination of Left-Right Asymmetry

Yoshioka, Hidefumi; Meno, Chikara; Koshiba, Kazuko; Sugihara, Minoru; Itoh, Hiroyuki; Ishimaru, Yoshiyasu; Inoue, Takashi; Ohuchi, Hideyo; Semina, Elena V.; Murray, Jeffrey C.; Hamada, Hiroshi; Noji, Sumihare

doi:10.1016/s0092-8674(00)81473-7

Cited by 351 publications

(256 citation statements)

References 24 publications

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“…There are several measures of incorrect gene expression that have been reported in the literature (Sampath et al, 1997; Yoshioka et al, 1998; Levin et al, 1995): right-sided and bilateral expression of these genes is incorrect; some treatments also induce absence of gene expression in treated embryos. Absent expression of a typically asymmetric gene is particularly perplexing because there is little discussion in the literature about how lack of expression should affect organ situs.…”

Section: Resultsmentioning

confidence: 99%

Laterality defects are influenced by timing of treatments and animal model

Vandenberg

2012

Differentiation

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The timing of when the embryonic left-right (LR) axis is first established and the mechanisms driving this process are subjects of strong debate. While groups have focused on the role of cilia in establishing the LR axis during gastrula and neurula stages, many animals appear to orient the LR axis prior to the appearance of, or without the benefit of, motile cilia. Because of the large amount of data available in the published literature and the similarities in the type of data collected across labs, I have examined relationships between the studies that do and do not implicate cilia, the choice of animal model, the kinds of LR patterning defects observed, and the penetrance of LR phenotypes. I found that treatments affecting cilia structure and motility had a higher penetrance for both altered gene expression and improper organ placement compared to treatments that affect processes in early cleavage stage embryos. I also found differences in penetrance that could be attributed to the animal models used; the mouse is highly prone to LR randomization. Additionally, the data were examined to address whether gene expression can be used to predict randomized organ placement. Using regression analysis, gene expression was found to be predictive of organ placement in frogs, but much less so in the other animals examined. Together, these results challenge previous ideas about the conservation of LR mechanisms, with the mouse model being significantly different from fish, frogs and chick in almost every aspect examined. Additionally, this analysis indicates that there may be missing pieces in the molecular pathways that dictate how genetic information becomes organ positional information in vertebrates; these gaps will be important for future studies to identify, as LR asymmetry is not only a fundamentally fascinating aspect of development but also of considerable biomedical importance.

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Section: Resultsmentioning

confidence: 99%

Laterality defects are influenced by timing of treatments and animal model

Vandenberg

2012

Differentiation

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“…RNA probes for Nodal, Lefty (which recognizes Lefty1 and Lefty2), and Pitx2 have been described previously (Lowe et al, 1996;Meno et al, 1996;Yoshioka et al, 1998). The Mgrn1 probe was a 420-bp portion of the 3Ј untranslated region (common to all four isoforms) generated by polymerase chain reaction using forward primer CAGTTCCCCCGCACAGGTC and reverse primer AGGAAGGAGCAGGG-TTAGAGTCAG and IMAGE cDNA clone 3481878 as template.…”

Section: Whole-mount In Situ Hybridizationmentioning

confidence: 99%

“…The LR axis is the final of the three body axes to be established during development, with the initial symmetry-breaking event occurring at the late neural fold stage . Over the past decade, several genes involved in these steps have been identified, including those encoding the transforming growth factor-␤-related signaling molecules Nodal, Lefty1, and Lefty2 and the bicoid-type homeobox gene Pitx2 (Collignon et al, 1996;Lowe et al, 1996;Meno et al, 1998;Yoshioka et al, 1998). The initial symmetrybreaking event has been attributed to a leftward flow that is a result of beating monocilia located on the ventral surface of the node in mammals.…”

Section: Introductionmentioning

confidence: 99%

Mice with mutations in Mahogunin ring finger‐1 (Mgrn1) exhibit abnormal patterning of the left–right axis

Cota

Bagher

Pelc

et al. 2006

Developmental Dynamics

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Mahogunin Ring Finger 1 (Mgrn1) encodes a RING-containing protein with ubiquitin ligase activity that has been implicated in pigment-type switching. In addition to having dark fur, mice lacking MGRN1 develop adult-onset spongy degeneration of the central nervous system and have reduced embryonic viability. Observation of complete situs inversus in a small proportion of adult Mgrn1 mutant mice suggested that embryonic lethality resulted from congenital heart defects due to defective establishment and/or maintenance of the left-right (LR) axis. Here we report that Mgrn1 is expressed in a pattern consistent with a role in LR patterning during early development and that many Mgrn1 mutant embryos show abnormal expression of asymmetrically expressed genes involved in LR patterning. A range of complex heart defects was observed in 20 -25% of mid-to-late gestation Mgrn1 mutant embryos and another 20% were dead. This finding was consistent with 46 -60% mortality of mutants by weaning age. Our results indicate that Mgrn1 acts early in the LR signaling cascade and is likely to provide new insight into this developmental process as Nodal expression was uncoupled from expression of other Nodal-responsive genes in Mgrn1 mutant embryos. Our work identifies a novel role for MGRN1 in embryonic patterning and suggests that the ubiquitination of MGRN1 target genes is essential for the proper establishment and/or maintenance of the LR axis. Developmental Dynamics 235:3438 -3447, 2006.

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“…pitx2 appears to be one of the early factors contributing to the execution of LR instructions during tissue morphogenesis, and has been shown to be necessary for asymmetric morphogenesis of the lung and heart (Logan et al, 1998;Piedra et al, 1998;Ryan et al, 1998;St Amand et al, 1998;Yoshioka et al, 1998;Piedra and Ros, 2002). There are still large gaps in understanding the asymmetric morphogenesis of the visceral organs, of which many are of endodermal origin.…”

Section: Introductionmentioning

confidence: 99%

A mutation in the zebrafish Na,K‐ATPase subunit atp1a1a.1 provides genetic evidence that the sodium potassium pump contributes to left‐right asymmetry downstream or in parallel to nodal flow

Ellertsdóttir

Ganz

Dürr

et al. 2006

Developmental Dynamics

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While there is a good conceptual framework of dorsoventral and anterioposterior axes formation in most vertebrate groups, understanding of left-right axis initiation is fragmentary. Diverse mechanisms have been implied to contribute to the earliest steps of left-right asymmetry, including small molecule signals, gap junctional communication, membrane potential, and directional flow of extracellular liquid generated by monocilia in the node region. Here we demonstrate that a mutation in the zebrafish Na,K-ATPase subunit atp1a1a causes left-right defects including isomerism of internal organs at the anatomical level. The normally left-sided Nodal signal spaw as well as its inhibitor lefty are expressed bilaterally, while pitx2 may appear random or bilateral. Monocilia movement and fluid circulation in Kupffer's vesicle are normal in atp1a1a m883 mutant embryos. Therefore, the Na,K-ATPase is required downstream or in parallel to monocilia function during initiation of left-right asymmetry in zebrafish.

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Pitx2, a Bicoid-Type Homeobox Gene, Is Involved in a Lefty-Signaling Pathway in Determination of Left-Right Asymmetry

Cited by 351 publications

References 24 publications

Laterality defects are influenced by timing of treatments and animal model

Laterality defects are influenced by timing of treatments and animal model

Mice with mutations in Mahogunin ring finger‐1 (Mgrn1) exhibit abnormal patterning of the left–right axis

A mutation in the zebrafish Na,K‐ATPase subunit atp1a1a.1 provides genetic evidence that the sodium potassium pump contributes to left‐right asymmetry downstream or in parallel to nodal flow

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