The homeobox gene Pitx2: mediator of asymmetric left-right signaling in vertebrate heart and gut looping

Development ◽  
1999 ◽  
Vol 126 (6) ◽  
pp. 1225-1234 ◽  
Author(s):  
M. Campione ◽  
H. Steinbeisser ◽  
A. Schweickert ◽  
K. Deissler ◽  
F. van Bebber ◽  
...  
Keyword(s):  
Ectopic Expression ◽  
Homeobox Gene ◽  
Zebrafish Embryos ◽  
Lateral Plate Mesoderm ◽  
Lateral Plate ◽  
Left Right Asymmetry ◽  
The Right ◽  
Pitx2 Expression

Left-right asymmetry in vertebrates is controlled by activities emanating from the left lateral plate. How these signals get transmitted to the forming organs is not known. A candidate mediator in mouse, frog and zebrafish embryos is the homeobox gene Pitx2. It is asymmetrically expressed in the left lateral plate mesoderm, tubular heart and early gut tube. Localized Pitx2 expression continues when these organs undergo asymmetric looping morphogenesis. Ectopic expression of Xnr1 in the right lateral plate induces Pitx2 transcription in Xenopus. Misexpression of Pitx2 affects situs and morphology of organs. These experiments suggest a role for Pitx2 in promoting looping of the linear heart and gut.

Zic3 is involved in the left-right specification of the Xenopus embryo

Development ◽  
2000 ◽  
Vol 127 (22) ◽  
pp. 4787-4795 ◽  
Author(s):  
T. Kitaguchi ◽  
T. Nagai ◽  
K. Nakata ◽  
J. Aruga ◽  
K. Mikoshiba
Keyword(s):  
Molecular Basis ◽  
Xenopus Embryo ◽  
Zinc Finger Domain ◽  
Lateral Plate Mesoderm ◽  
Vertebrate Development ◽  
Gastrula Stage ◽  
Lateral Plate ◽  
The Right ◽  
Early Gastrula ◽  
Pitx2 Expression

Establishment of left-right (L-R) asymmetry is fundamental to vertebrate development. Several genes involved in L-R asymmetry have been described. In the Xenopus embryo, Vg1/activin signals are implicated upstream of asymmetric nodal related 1 (Xnr1) and Pitx2 expression in L-R patterning. We report here that Zic3 carries the left-sided signal from the initial activin-like signal to determinative factors such as Pitx2. Overexpression of Zic3 on the right side of the embryo altered the orientation of heart and gut looping, concomitant with disturbed laterality of expression of Xnr1 and Pitx2, both of which are normally expressed in the left lateral plate mesoderm. The results indicate that Zic3 participates in the left-sided signaling upstream of Xnr1 and Pitx2. At early gastrula, Zic3 was expressed not only in presumptive neuroectoderm but also in mesoderm. Correspondingly, overexpression of Zic3 was effective in the L-R specification at the early gastrula stage, as revealed by a hormone-inducible Zic3 construct. The Zic3 expression in the mesoderm is induced by activin (beta) or Vg1, which are also involved in the left-sided signal in L-R specification. These findings suggest that an activin-like signal is a potent upstream activator of Zic3 that establishes the L-R axis. Furthermore, overexpression of the zinc-finger domain of Zic3 on the right side is sufficient to disturb the L-R axis, while overexpression of the N-terminal domain on the left side affects the laterality. These results suggest that Zic3 has at least two functionally important domains that play different roles and provide a molecular basis for human heterotaxy, which is an L-R pattern anomaly caused by a mutation in human ZIC3.

Regulation of midline development by antagonism of lefty and nodal signaling

Development ◽  
1999 ◽  
Vol 126 (14) ◽  
pp. 3253-3262 ◽  
Author(s):  
B.W. Bisgrove ◽  
J.J. Essner ◽  
H.J. Yost
Keyword(s):  
Expression Patterns ◽  
Ectopic Expression ◽  
Bilateral Symmetry ◽  
Expression Domain ◽  
Lateral Plate ◽  
Altered Expression ◽  
Left Right Asymmetry ◽  
Midline Development ◽  
Additional Role ◽  
Pitx2 Expression

The embryonic midline is crucial for the development of embryonic pattern including bilateral symmetry and left-right asymmetry. In zebrafish, lefty1 (lft1) and lefty2 (lft2) have distinct midline expression domains along the anteroposterior axis that overlap with the expression patterns of the nodal-related genes cyclops and squint. Altered expression patterns of lft1 and lft2 in zebrafish mutants that affect midline development suggests different upstream pathways regulate each expression domain. Ectopic expression analysis demonstrates that a balance of lefty and cyclops signaling is required for normal mesendoderm patterning and goosecoid, no tail and pitx2 expression. In late somite-stage embryos, lft1 and lft2 are expressed asymmetrically in the left diencephalon and left lateral plate respectively, suggesting an additional role in laterality development. A model is proposed by which the vertebrate midline, and thus bilateral symmetry, is established and maintained by antagonistic interactions among co-expressed members of the lefty and nodal subfamilies of TGF-beta signaling molecules.

BMP signaling positively regulates Nodal expression during left right specification in the chick embryo

Development ◽  
2002 ◽  
Vol 129 (14) ◽  
pp. 3431-3440 ◽  
Author(s):  
M. Elisa Piedra ◽  
Mana A. Ros
Keyword(s):  
Bmp Signaling ◽  
Lateral Plate Mesoderm ◽  
Lateral Plate ◽  
Positive Role ◽  
Molecular Control ◽  
Left And Right ◽  
Left Right Asymmetry ◽  
The Right ◽  
Rapid Activation ◽  
Positive Effect

Exogenous application of BMP to the lateral plate mesoderm (LPM) of chick embryos at the early somite stage had a positive effect on Nodal expression. BMP applications into the right LPM were followed by a rapid activation of Nodal, while applications into the left LPM resulted in expansion of the normal domain of Nodal expression. Conversely, blocking of BMP signaling by Noggin in the left LPM interfered with the activation of Nodal expression. These results support a positive role for endogenous BMP on Nodal expression in the LPM. We also report that BMP positively regulates the expression of Caronte, Snail and Cfc in both the left and right LPM. BMP-treated embryos had molecular impairment of the midline with downregulation of Lefty1, Brachyury and Shh but we also show that the midline defect was not sufficient to induce ectopic Nodal expression. We discuss our findings in the context of the known molecular control of the specification of left-right asymmetry.

scholarly journals A Xenopus nodal-related gene that acts in synergy with noggin to induce complete secondary axis and notochord formation

Development ◽  
1996 ◽  
Vol 122 (10) ◽  
pp. 3275-3282 ◽  
Author(s):  
K.D. Lustig ◽  
K. Kroll ◽  
E. Sun ◽  
R. Ramos ◽  
H. Elmendorf ◽  
...  
Keyword(s):  
Ectopic Expression ◽  
Signaling Proteins ◽  
Secreted Protein ◽  
Lateral Plate Mesoderm ◽  
Related Gene ◽  
Lateral Plate ◽  
Secondary Axis ◽  
Muscle Formation ◽  
Tailbud Stage ◽  
Left Right Asymmetry

Using a paracrine assay to screen for signaling proteins that could respecify ectodermal tissue, we isolated a Xenopus gene related to the mouse gene nodal, a member of the TGFbeta superfamily. The gene is expressed in three regions in the early Xenopus embryo: first in the gastrula organizer, then in two stripes of cells flanking the posterior notochord in late neurulae, and finally in lateral plate mesoderm restricted to the left side of tailbud-stage embryos. Ectopic expression of the gene induces muscle formation in ectodermal explants and partial secondary axes in whole embryos. Together with noggin, another secreted protein also present in the organizer, it induces notochord formation in ectodermal explants and complete secondary axes in whole embryos. These results suggest that the nodal-related gene may act together with noggin to induce axial pattern during gastrulation and also may play a role in left-right asymmetry generation in the post-gastrula embryo.

scholarly journals Antagonistic interactions in the zebrafish midline prior to the emergence of asymmetric gene expression are important for left–right patterning

2016 ◽  
Vol 371 (1710) ◽  
pp. 20150402 ◽  
Author(s):  
Rebecca D. Burdine ◽  
Daniel T. Grimes
Keyword(s):  
Gene Expression ◽  
Lateral Plate Mesoderm ◽  
Internal Organs ◽  
Lateral Plate ◽  
Left Right Asymmetry ◽  
Antagonistic Interactions

Left–right (L-R) asymmetry of the internal organs of vertebrates is presaged by domains of asymmetric gene expression in the lateral plate mesoderm (LPM) during somitogenesis. Ciliated L-R coordinators (LRCs) are critical for biasing the initiation of asymmetrically expressed genes, such as nodal and pitx2 , to the left LPM. Other midline structures, including the notochord and floorplate, are then required to maintain these asymmetries. Here we report an unexpected role for the zebrafish EGF-CFC gene one-eyed pinhead ( oep ) in the midline to promote pitx2 expression in the LPM. Late zygotic oep (LZ oep ) mutants have strongly reduced or absent pitx2 expression in the LPM, but this expression can be rescued to strong levels by restoring oep in midline structures only. Furthermore, removing midline structures from LZ oep embryos can rescue pitx2 expression in the LPM, suggesting the midline is a source of an LPM pitx2 repressor that is itself inhibited by oep . Reducing lefty1 activity in LZ oep embryos mimics removal of the midline, implicating lefty1 in the midline-derived repression. Together, this suggests a model where Oep in the midline functions to overcome a midline-derived repressor, involving lefty1 , to allow for the expression of left side-specific genes in the LPM. This article is part of the themed issue ‘Provocative questions in left–right asymmetry’.

scholarly journals Gut endoderm is involved in the transfer of left-right asymmetry from the node to the lateral plate mesoderm in the mouse embryo

Development ◽  
2012 ◽  
Vol 139 (13) ◽  
pp. 2426-2435 ◽  
Author(s):  
R. S. Saund ◽  
M. Kanai-Azuma ◽  
Y. Kanai ◽  
I. Kim ◽  
M. T. Lucero ◽  
...  
Keyword(s):  
Mouse Embryo ◽  
Lateral Plate Mesoderm ◽  
Lateral Plate ◽  
Left Right Asymmetry ◽  
Gut Endoderm

The Xenopus homeobox gene pitx3 impinges upon somitogenesis and laterality

2013 ◽  
Vol 91 (2) ◽  
pp. 79-87 ◽  
Author(s):  
Cristine Smoczer ◽  
Lara Hooker ◽  
Sarah Brode ◽  
Marian Wolanski ◽  
Farhad KhosrowShahian ◽  
...  
Keyword(s):  
Anterior Segment ◽  
Homeobox Gene ◽  
The Other ◽  
Lateral Plate Mesoderm ◽  
Lateral Plate ◽  
Anterior Segment Dysgenesis ◽  
Cellular Changes ◽  
Causative Locus ◽  
Dorsal Axis ◽  
Vertebral Anomalies

Pitx3 has been identified as the causative locus in a developmental eye mutation associated with mammalian anterior segment dysgenesis, congenital cataracts, and aphakia. In recent studies of frog eye development we discovered that pitx3 expresses symmetrically in the somites and lateral plate mesoderm and asymmetrically during cardiac and gut looping. We report that disruption of pitx3 activity on one side of an embryo relative to the other, either by over- or underexpression of pitx3, elicits a crooked dorsal axis in embryos that is a consequence of a retarded progression through somitogenesis. Unlike in amniotes, Xenopus somites form as cohorts of presomitic cells that rotate perpendicular to the dorsal axis. Since no vertebral anomalies have been reported in mouse and human Pitx3 mutants, we attempt to distinguish whether the segmentation clock is uniquely affected in frog or if the pitx3 perturbation inhibits the cellular changes that are necessary to rotation of presomitic cells. In Xenopus, pitx3 appears to inhibit the rotation of presomitic cell cohorts and to be necessary to the bilaterally symmetric expression of pitx2 in somites.

The forkhead transcription factor Foxf1 is required for differentiation of extra-embryonic and lateral plate mesoderm

Development ◽  
2001 ◽  
Vol 128 (2) ◽  
pp. 155-166 ◽  
Author(s):  
M. Mahlapuu ◽  
M. Ormestad ◽  
S. Enerback ◽  
P. Carlsson
Keyword(s):  
Transcription Factor ◽  
Cell Adhesion ◽  
Posterior Part ◽  
Homeobox Gene ◽  
Primitive Streak ◽  
Yolk Sac ◽  
Lateral Plate Mesoderm ◽  
Forkhead Transcription Factor ◽  
Lateral Plate ◽  
Adhesion Properties

The murine Foxf1 gene encodes a forkhead transcription factor expressed in extra-embryonic and lateral plate mesoderm and later in splanchnic mesenchyme surrounding the gut and its derivatives. We have disrupted Foxf1 and show that mutant embryos die at midgestation due to defects in mesodermal differentiation and cell adhesion. The embryos do not turn and become deformed by the constraints of a small, inflexible amnion. Extra-embryonic structures exhibit a number of differentiation defects: no vasculogenesis occurs in yolk sac or allantois; chorioallantoic fusion fails; the amnion does not expand with the growth of the embryo, but misexpresses vascular and hematopoietic markers. Separation of the bulk of yolk sac mesoderm from the endodermal layer and adherence between mesoderm of yolk sac and amnion, indicate altered cell adhesion properties and enhanced intramesodermal cohesion. A possible cause of this is misexpression of the cell-adhesion protein VCAM1 in Foxf1-deficient extra-embryonic mesoderm, which leads to co-expression of VCAM with its receptor, alpha(4)-integrin. The expression level of Bmp4 is decreased in the posterior part of the embryo proper. Consistent with this, mesodermal proliferation in the primitive streak is reduced and somite formation is retarded. Expression of Foxf1 and the homeobox gene Irx3 defines the splanchnic and somatic mesodermal layers, respectively. In Foxf1-deficient embryos incomplete separation of splanchnic and somatic mesoderm is accompanied by misexpression of Irx3 in the splanchnopleure, which implicates Foxf1 as a repressor of Irx3 and as a factor involved in coelom formation.

Hindlimb patterning and mandible development require the Ptx1 gene

Development ◽  
1999 ◽  
Vol 126 (9) ◽  
pp. 1805-1810 ◽  
Author(s):  
C. Lanctot ◽  
A. Moreau ◽  
M. Chamberland ◽  
M.L. Tremblay ◽  
J. Drouin
Keyword(s):  
Gene Knockout ◽  
Proximal Part ◽  
Branchial Arch ◽  
Dorsal Side ◽  
Lateral Plate Mesoderm ◽  
Lateral Plate ◽  
Similar Time ◽  
The Right ◽  
Tetrapod Evolution

The restricted expression of the Ptx1 (Pitx1) gene in the posterior half of the lateral plate mesoderm has suggested that it may play a role in specification of posterior structures, in particular, specification of hindlimb identity. Ptx1 is also expressed in the most anterior ectoderm, the stomodeum, and in the first branchial arch. Ptx1 expression overlaps with that of Ptx2 in stomodeum and in posterior left lateral plate mesoderm. We now show that targeted inactivation of the mouse Ptx1 gene severely impairs hindlimb development: the ilium and knee cartilage are absent and the long bones are underdeveloped. Greater reduction of the right femur size in Ptx1 null mice suggests partial compensation by Ptx2 on the left side. The similarly sized tibia and fibula of mutant hindlimbs may be taken to resemble forelimb bones: however, the mutant limb buds appear to have retained their molecular identity as assessed by forelimb expression of Tbx5 and by hindlimb expression of Tbx4, even though Tbx4 expression is decreased in Ptx1 null mice. The hindlimb defects appear to be, at least partly, due to abnormal chondrogenesis. Since the most affected structures derive from the dorsal side of hindlimb buds, the data suggest that Ptx1 is responsible for patterning of these dorsal structures and that as such it may control development of hindlimb-specific features. Ptx1 inactivation also leads to loss of bones derived from the proximal part of the mandibular mesenchyme. The dual role of Ptx1 revealed by the gene knockout may reflect features of the mammalian jaw and hindlimbs that were acquired at a similar time during tetrapod evolution.

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