Genomes and Genes
Gene Symbol: pitx2
Description: paired-like homeodomain 2
Alias: pitx2a, pitx2c, zgc:110508, pituitary homeobox 2, homeobox protein PITX2, paired-like homeodomain transcription factor 2, paired-like homeodomain transcription factor 2a, pitx2b
- Essner J, Branford W, Zhang J, Yost H. Mesendoderm and left-right brain, heart and gut development are differentially regulated by pitx2 isoforms. Development. 2000;127:1081-93 pubmed..Here we demonstrate that in zebrafish there are two pitx2 isoforms, pitx2a and pitx2c, which show distinct expression patterns and have non-overlapping functions during mesendoderm and asymmetric ..
- Wang X, Yost H. Initiation and propagation of posterior to anterior (PA) waves in zebrafish left-right development. Dev Dyn. 2008;237:3640-7 pubmed publisher..describe the timing of the posterior to anterior (PA) wave-like propagation of zebrafish southpaw (Nodal) and pitx2 in LPM and lefty1 in the midline...
- Snelson C, Santhakumar K, Halpern M, Gamse J. Tbx2b is required for the development of the parapineal organ. Development. 2008;135:1693-702 pubmed publisher..We conclude that tbx2b functions to specify the correct number of parapineal cells and to regulate their asymmetric migration. ..
- Kramer Zucker A, Olale F, Haycraft C, Yoder B, Schier A, Drummond I. Cilia-driven fluid flow in the zebrafish pronephros, brain and Kupffer's vesicle is required for normal organogenesis. Development. 2005;132:1907-21 pubmed..In Kupffer's vesicle, loss of flow is associated with loss of left-right patterning, indicating that the 'nodal flow' mechanism of generating situs is conserved in non-mammalian vertebrates. ..
- Campione M, Steinbeisser H, Schweickert A, Deissler K, van Bebber F, Lowe L, et al. The homeobox gene Pitx2: mediator of asymmetric left-right signaling in vertebrate heart and gut looping. Development. 1999;126:1225-34 pubmed..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...
- Ablooglu A, Kang J, Handin R, Traver D, Shattil S. The zebrafish vitronectin receptor: characterization of integrin alphaV and beta3 expression patterns in early vertebrate development. Dev Dyn. 2007;236:2268-76 pubmed..Furthermore, when beta3.1 expression profiles are compared to those of other potential alphaV partners (beta1, beta5, and beta8), pharyngeal dentitions appear to represent a unique expression field for alphaV and beta3.1. ..
- Tay H, Schulze S, Compagnon J, Foley F, Heisenberg C, Yost H, et al. Lethal giant larvae 2 regulates development of the ciliated organ Kupffer's vesicle. Development. 2013;140:1550-9 pubmed publisher..These results uncover new roles and interactions for Lgl2 that are crucial for both lumenogenesis and ciliogenesis and indicate that these processes are genetically separable in zebrafish. ..
- Jackman W, Draper B, Stock D. Fgf signaling is required for zebrafish tooth development. Dev Biol. 2004;274:139-57 pubmed..While the pharyngeal epithelium remained intact as judged by normal pitx2 expression, not only was the mesenchymal expression of lhx6 and lhx7 eliminated as expected from mouse studies, ..
- Concha M, Burdine R, Russell C, Schier A, Wilson S. A nodal signaling pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain. Neuron. 2000;28:399-409 pubmed..This indicates that Nodal signaling is not required for asymmetric development per se but is essential to determine the laterality of the asymmetry. ..
- Monteiro R, Van Dinther M, Bakkers J, Wilkinson R, Patient R, Ten Dijke P, et al. Two novel type II receptors mediate BMP signalling and are required to establish left-right asymmetry in zebrafish. Dev Biol. 2008;315:55-71 pubmed publisher..Expression of early laterality markers in morphants indicated that bmpr2a and bmpr2b act upstream of pitx2 and the nodal-related southpaw (spaw), which are expressed asymmetrically in the lateral plate mesoderm (LPM), and ..
- Carl M, Bianco I, Bajoghli B, Aghaallaei N, Czerny T, Wilson S. Wnt/Axin1/beta-catenin signaling regulates asymmetric nodal activation, elaboration, and concordance of CNS asymmetries. Neuron. 2007;55:393-405 pubmed..We identify a second role for the Wnt pathway in the left/right regulation of LPM Nodal pathway gene expression, and finally, we show that at later stages Axin1 is required for the elaboration of concordant neuroanatomical asymmetries. ..
- RoussignÃ© M, Bianco I, Wilson S, Blader P. Nodal signalling imposes left-right asymmetry upon neurogenesis in the habenular nuclei. Development. 2009;136:1549-57 pubmed publisher..Our results provide evidence of a direct requirement for unilateral Nodal activity in establishing an asymmetry per se, rather than solely in biasing its laterality. ..
- Saude L, Lourenço R, Gonçalves A, Palmeirim I. terra is a left-right asymmetry gene required for left-right synchronization of the segmentation clock. Nat Cell Biol. 2005;7:918-20 pubmed..Here, we show that terra is an early left-sided expressed gene that links left-right patterning with bilateral synchronization of the segmentation clock. ..
- Stock D. Zebrafish dentition in comparative context. J Exp Zool B Mol Dev Evol. 2007;308:523-49 pubmed..Such studies may reveal the relative contribution to trends in dental evolution of biases in the generation of variation and sorting of this variation by selection or drift...
- Panizzi J, Jessen J, Drummond I, Solnica Krezel L. New functions for a vertebrate Rho guanine nucleotide exchange factor in ciliated epithelia. Development. 2007;134:921-31 pubmed..Our studies in zebrafish embryos have identified new, essential roles for this RhoGEF in ciliated epithelia during vertebrate development...
- Garric L, Ronsin B, Roussigne M, Booton S, Gamse J, Dufourcq P, et al. Pitx2c ensures habenular asymmetry by restricting parapineal cell number. Development. 2014;141:1572-9 pubmed publisher..The Nodal target pitx2c is expressed in the left epithalamus, but nothing is known about its role during the establishment of asymmetry in ..
- Essner J, Amack J, Nyholm M, Harris E, Yost H. Kupffer's vesicle is a ciliated organ of asymmetry in the zebrafish embryo that initiates left-right development of the brain, heart and gut. Development. 2005;132:1247-60 pubmed..These results suggest that cilia are an essential component of a conserved mechanism that controls the transition from bilateral symmetry to LR asymmetry in vertebrates. ..
- Zhao Y, Yang Z, Phelan J, Wheeler D, Lin S, McCabe E. Zebrafish dax1 is required for development of the interrenal organ, the adrenal cortex equivalent. Mol Endocrinol. 2006;20:2630-40 pubmed..Based on these results, we propose that dax1 is the mammalian DAX1 ortholog, functions downstream of ff1b in the regulatory cascades, and is required for normal development and function of the zebrafish interrenal organ...
- Yamauchi H, Miyakawa N, Miyake A, Itoh N. Fgf4 is required for left-right patterning of visceral organs in zebrafish. Dev Biol. 2009;332:177-85 pubmed publisher..Lefty1, lefty2, southpaw, and pitx2 are known to play crucial roles in LR patterning of visceral organs...
- Park S, Lee Y, Seki T, Hong K, Fliess N, Jiang Z, et al. ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2. Blood. 2008;111:633-42 pubmed..These data indicate that neither ALK5 nor TGFBR2 is required for ALK1 signaling pertinent to the pathogenesis of HHT and suggest that HHT might not be a TGF-beta subfamily disease. ..
- Hashimoto H, Rebagliati M, Ahmad N, Muraoka O, Kurokawa T, Hibi M, et al. The Cerberus/Dan-family protein Charon is a negative regulator of Nodal signaling during left-right patterning in zebrafish. Development. 2004;131:1741-53 pubmed publisher..of the left side-specific genes in the lateral plate mesoderm (southpaw, cyclops, atv/lefty1, lefty2 and pitx2) and diencephalon (cyclops, atv/lefty1 and pitx2), and defects in early (heart jogging) and late (heart looping) ..
- Lopes S, Lourenço R, Pacheco L, Moreno N, Kreiling J, Saude L. Notch signalling regulates left-right asymmetry through ciliary length control. Development. 2010;137:3625-32 pubmed publisher..Notch signalling brings together ciliary length control and fluid flow hydrodynamics with transcriptional activation of laterality genes. In addition, our deltaD mutant analysis discloses an uncoupling between gut and heart laterality. ..
- Chocron S, Verhoeven M, Rentzsch F, Hammerschmidt M, Bakkers J. Zebrafish Bmp4 regulates left-right asymmetry at two distinct developmental time points. Dev Biol. 2007;305:577-88 pubmed..The identification of these two distinct and opposing activities of BMP signaling provides new insight into how BMP signaling can regulate LR patterning. ..
- Balczerski B, Matsutani M, Castillo P, Osborne N, Stainier D, Crump J. Analysis of sphingosine-1-phosphate signaling mutants reveals endodermal requirements for the growth but not dorsoventral patterning of jaw skeletal precursors. Dev Biol. 2012;362:230-41 pubmed publisher..Hence, we propose that the S1P-dependent anterior foregut endoderm functions primarily through Shh to regulate the growth but not DV patterning of zebrafish jaw precursors...
- Lu P, Lund C, Khuansuwan S, Schumann A, Harney Tolo M, Gamse J, et al. Failure in closure of the anterior neural tube causes left isomerization of the zebrafish epithalamus. Dev Biol. 2013;374:333-44 pubmed publisher..This mechanism fails when the two sides of the epithalamus are widely separated from one another, suggesting that it is dependent upon a signaling protein with limited range. ..
- Peeters H, Voz M, Verschueren K, De Cat B, Pendeville H, Thienpont B, et al. Sesn1 is a novel gene for left-right asymmetry and mediating nodal signaling. Hum Mol Genet. 2006;15:3369-77 pubmed..In this study, we identify SESN1 as an indispensable gene for vertebrate left-right asymmetry and a new player in mediating Nodal signaling. ..
- Wang L, Liu Z, Lin H, Ma D, Tao Q, Liu F. Epigenetic regulation of left-right asymmetry by DNA methylation. EMBO J. 2017;36:2987-2997 pubmed publisher..1 regulates collective DFC migration through cadherin 1 (Cdh1). Taken together, our data uncover dynamic DNA methylation as an epigenetic mechanism to control LR determination during early embryogenesis in vertebrates. ..
- Müller I, Melville D, Tanwar V, Rybski W, Mukherjee A, Shoemaker M, et al. Functional modeling in zebrafish demonstrates that the atrial-fibrillation-associated gene GREM2 regulates cardiac laterality, cardiomyocyte differentiation and atrial rhythm. Dis Model Mech. 2013;6:332-41 pubmed publisher..These results implicate, for the first time, regulators of BMP signaling in human AF, providing mechanistic insights into the pathogenesis of the disease and identifying potential new therapeutic targets. ..
- Tian T, Zhao L, Zhao X, Zhang M, Meng A. A zebrafish gene trap line expresses GFP recapturing expression pattern of foxj1b. J Genet Genomics. 2009;36:581-9 pubmed publisher..Nevertheless, this transgenic line may serve as a useful model for dynamic observation of GFP-labeled tissues and organs and for isolation of GFP-labeled cells. ..
- John L, Trengove M, Fraser F, Yoong S, Ward A. Pegasus, the 'atypical' Ikaros family member, influences left-right asymmetry and regulates pitx2 expression. Dev Biol. 2013;377:46-54 pubmed publisher..One of these, pitx2, implicated in left-right asymmetry, possessed appropriate 'atypical' Pegasus binding sites in its promoter...
- Oishi I, Kawakami Y, Raya A, Callol Massot C, Izpisua Belmonte J. Regulation of primary cilia formation and left-right patterning in zebrafish by a noncanonical Wnt signaling mediator, duboraya. Nat Genet. 2006;38:1316-22 pubmed
- Yang Q, Chen D, Xiong F, Chen D, Liu C, Liu Y, et al. A splicing mutation in VPS4B causes dentin dysplasia I. J Med Genet. 2016;53:624-33 pubmed publisher..This study identifies VPS4B as a disease-causing gene for DDI, which is one of the important contributors to tooth formation, through the Wnt/Î²-catenin signalling pathway. ..
- OcaÃ±a O, Coskun H, MinguillÃ³n C, Murawala P, Tanaka E, GalcerÃ¡n J, et al. A right-handed signalling pathway drives heart looping in vertebrates. Nature. 2017;549:86-90 pubmed publisher..In vertebrates, left identity is mediated by the left-specific Nodal-Pitx2 axis that is repressed on the right-hand side by the epithelial-mesenchymal transition (EMT) inducer Snail1 (refs ..
- Jin D, Ni T, Sun J, Wan H, Amack J, Yu G, et al. Prostaglandin signalling regulates ciliogenesis by modulating intraflagellar transport. Nat Cell Biol. 2014;16:841-51 pubmed publisher..These findings lead us to propose that Lkt/ABCC4-mediated PGE2 signalling acts through a ciliary G-protein-coupled receptor, EP4, to upregulate cAMP synthesis and increase anterograde IFT, thereby promoting ciliogenesis. ..
- Colombo A, Palma K, Armijo L, Mione M, Signore I, Morales C, et al. Daam1a mediates asymmetric habenular morphogenesis by regulating dendritic and axonal outgrowth. Development. 2013;140:3997-4007 pubmed publisher..Our results indicate that Daam1a plays a key role in asymmetric habenular morphogenesis mediating the growth of dendritic and axonal processes in dorsal habenular neurons. ..
- Wise S, Stock D. bmp2b and bmp4 are dispensable for zebrafish tooth development. Dev Dyn. 2010;239:2534-46 pubmed publisher..The mostly likely explanation for this result is functional redundancy with other Bmp ligands, which may differ between the zebrafish and the mouse. ..
- Barth K, Miklosi A, Watkins J, Bianco I, Wilson S, Andrew R. fsi zebrafish show concordant reversal of laterality of viscera, neuroanatomy, and a subset of behavioral responses. Curr Biol. 2005;15:844-50 pubmed..Revealing a link between visceral and brain asymmetry and lateralized behavior, our studies help to explain the complexity of the relationship between the lateralities of visceral and neural asymmetries. ..
- Signore I, Guerrero N, Loosli F, Colombo A, Villalón A, Wittbrodt J, et al. Zebrafish and medaka: model organisms for a comparative developmental approach of brain asymmetry. Philos Trans R Soc Lond B Biol Sci. 2009;364:991-1003 pubmed publisher..Together, these findings highlight the usefulness of zebrafish and medaka as comparative models to study the developmental mechanisms of epithalamic asymmetry in vertebrates. ..
- Powers J, Zhao Y, Lin S, McCabe E. The expression of nr0b1, the earliest gene in zebrafish tooth development, is a marker for human tooth and ameloblastoma formation. Dev Genes Evol. 2009;219:419-25 pubmed publisher..The association of NR0B1 and its protein product DAX1 with primary tooth development and ameloblastoma tumorigenesis is an association not previously described. ..
- Rikin A, Evans T. The tbx/bHLH transcription factor mga regulates gata4 and organogenesis. Dev Dyn. 2010;239:535-47 pubmed publisher..Transcript profiling experiments show that mga functions early to influence key regulators of mesendoderm, including tbx6, cas, and sox17. ..
- Tu C, Yang T, Huang H, Tsai H. Zebrafish arl6ip1 is required for neural crest development during embryogenesis. PLoS ONE. 2012;7:e32899 pubmed publisher..Although the embryonic expression pattern of ADP ribosylation factor-like 6 interacting protein 1 (Arl6ip1) has been reported, its function in neural crest development is unclear...
- Xiong F, Ji Z, Liu Y, Zhang Y, Hu L, Yang Q, et al. Mutation in SSUH2 Causes Autosomal-Dominant Dentin Dysplasia Type I. Hum Mutat. 2017;38:95-104 pubmed publisher..Taken together, our observations demonstrate that SSUH2 disrupts dental formation and that this novel gene, together with other odontogenesis genes, is involved in tooth development. ..
- Seritrakul P, Samarut E, Lama T, Gibert Y, Laudet V, Jackman W. Retinoic acid expands the evolutionarily reduced dentition of zebrafish. FASEB J. 2012;26:5014-24 pubmed publisher..anteriorly the expression patterns of genes normally expressed in the posterior tooth-forming region, such as pitx2 and dlx2b...
- Acharya M, Huang L, Fleisch V, Allison W, Walter M. A complex regulatory network of transcription factors critical for ocular development and disease. Hum Mol Genet. 2011;20:1610-24 pubmed publisherThe PITX2 'homeobox' and FOXC1 and FOXC2 'forkhead box' transcription factors are critical for eye development and cause human ocular diseases when mutated...
- Wiweger M, Zhao Z, van Merkesteyn R, Roehl H, Hogendoorn P. HSPG-deficient zebrafish uncovers dental aspect of multiple osteochondromas. PLoS ONE. 2012;7:e29734 pubmed publisher..The presence of the malformed and/or displaced teeth with abnormal enamel was declared by half of the respondents indicating that MO might indeed be also associated with dental problems. ..
- Gao W, Xu L, Guan R, Liu X, Han Y, Wu Q, et al. Wdr18 is required for Kupffer's vesicle formation and regulation of body asymmetry in zebrafish. PLoS ONE. 2011;6:e23386 pubmed publisher..in the visceral organs, which were preceded by the mis-expression of Nodal-related genes, including spaw and pitx2. Examination of morphants at earlier stages revealed that the KV had fewer and shorter cilia which are immotile ..
- McMahon C, Semina E, Link B. Using zebrafish to study the complex genetics of glaucoma. Comp Biochem Physiol C Toxicol Pharmacol. 2004;138:343-50 pubmed..With zebrafish, forward and reverse genetic approaches can be combined in order to identify critical genetic interactions required for normal and pathological events in the development and maintenance of the eye. ..
- Lange M, Kaynak B, Forster U, Tönjes M, Fischer J, Grimm C, et al. Regulation of muscle development by DPF3, a novel histone acetylation and methylation reader of the BAF chromatin remodeling complex. Genes Dev. 2008;22:2370-84 pubmed publisher..Furthermore, this shows that plant homeodomain proteins play a yet unexplored role in recruiting chromatin remodeling complexes to acetylated histones. ..
- Esguerra C, Nelles L, Vermeire L, Ibrahimi A, Crawford A, Derua R, et al. Ttrap is an essential modulator of Smad3-dependent Nodal signaling during zebrafish gastrulation and left-right axis determination. Development. 2007;134:4381-93 pubmed
- Wilson C, Nguyen C, Chen M, Yang J, Gacayan R, Huang J, et al. Fused has evolved divergent roles in vertebrate Hedgehog signalling and motile ciliogenesis. Nature. 2009;459:98-102 pubmed publisher..Our results delineate a new pathway for central pair apparatus assembly, identify common regulators of Hh signalling and motile ciliogenesis, and provide insights into the evolution of the Hh cascade. ..
- Gao Q, Zhang J, Wang X, Liu Y, He R, Liu X, et al. The signalling receptor MCAM coordinates apical-basal polarity and planar cell polarity during morphogenesis. Nat Commun. 2017;8:15279 pubmed publisher..Therefore, MCAM coordination of AB polarity and PCP provides insight into the general mechanisms of morphogenesis. ..
- Eberhart J, Swartz M, Crump J, Kimmel C. Early Hedgehog signaling from neural to oral epithelium organizes anterior craniofacial development. Development. 2006;133:1069-77 pubmed
- Shi G, Sohn K, Choi T, Choi D, Lee S, Ou B, et al. Expression of paired-like homeodomain transcription factor 2c (PITX2c) in epidermal keratinocytes. Exp Cell Res. 2010;316:3263-71 pubmed publisher..RT-PCR analysis showed that PITX2c isoform was predominantly expressed in a differentiation-dependent manner...
- Smith K, Noël E, Thurlings I, Rehmann H, Chocron S, Bakkers J. Bmp and nodal independently regulate lefty1 expression to maintain unilateral nodal activity during left-right axis specification in zebrafish. PLoS Genet. 2011;7:e1002289 pubmed publisher..When nodal flow has been established and Nodal activity is apparent, both Nodal and Bmp independently are required for lefty1 expression to assure unilateral Nodal activation and correct LR patterning. ..
- Burkhalter M, Fralish G, Premont R, Caron M, Philipp M. Grk5l controls heart development by limiting mTOR signaling during symmetry breaking. Cell Rep. 2013;4:625-32 pubmed publisher..These findings could implicate GRK5 as a susceptibility allele for certain cases of CHD. ..
- Wang W, Zhang L, Gui Y, Song H. Retinol dehydrogenase, RDH1l, is essential for the heart development and cardiac performance in zebrafish. Chin Med J (Engl). 2013;126:722-8 pubmed..These results show for the first time that an enzyme involved in the retinol to retinaldehyde conversion participate in the heart development and cardiac performance in zebrafish. ..
- Moriarty M, Ryan R, Lalor P, Dockery P, Byrnes L, Grealy M. Loss of plakophilin 2 disrupts heart development in zebrafish. Int J Dev Biol. 2012;56:711-8 pubmed publisher..These results indicate that plakophilin 2 has both structural and signalling roles in zebrafish heart development. ..
- Gibert Y, Bernard L, Debiais Thibaud M, Bourrat F, Joly J, Pottin K, et al. Formation of oral and pharyngeal dentition in teleosts depends on differential recruitment of retinoic acid signaling. FASEB J. 2010;24:3298-309 pubmed publisher..The loss of pharyngeal teeth in this group was cancelled out through a shift in aldh1a2 expression, while oral teeth might have been lost ultimately due to deficient RA signaling in the oral cavity...
- Eason J, Williams A, Chawla B, Apsey C, Bohnsack B. Differences in neural crest sensitivity to ethanol account for the infrequency of anterior segment defects in the eye compared with craniofacial anomalies in a zebrafish model of fetal alcohol syndrome. Birth Defects Res. 2017;109:1212-1227 pubmed publisher..However, ETOH had minimal effect on the periocular and ocular expression of transcription factors (pitx2 and foxc1) that regulate anterior segment development...
- Eberhart J, He X, Swartz M, Yan Y, Song H, Boling T, et al. MicroRNA Mirn140 modulates Pdgf signaling during palatogenesis. Nat Genet. 2008;40:290-8 pubmed publisher..Concomitantly, the oral ectoderm beneath where these cartilages develop lost pitx2 and shha expression...
- Kang N, Ro H, Park Y, Kim H, Huh T, Rhee M. Seson, a novel zinc finger protein, controls cilia integrity for the LR patterning during zebrafish embryogenesis. Biochem Biophys Res Commun. 2010;401:169-74 pubmed publisher..Seson function was also required for ciliogenesis in other tissues such as the pronephros and olfactory organs. Collectively, our data suggest that Seson has critical roles in ciliogenesis and LR body axis patterning. ..
- Hoshijima K, Metherall J, Grunwald D. A protein disulfide isomerase expressed in the embryonic midline is required for left/right asymmetries. Genes Dev. 2002;16:2518-29 pubmed
- Kawakami Y, Raya A, Raya R, Rodriguez Esteban C, Izpisua Belmonte J. Retinoic acid signalling links left-right asymmetric patterning and bilaterally symmetric somitogenesis in the zebrafish embryo. Nature. 2005;435:165-71 pubmed
- Kreiling J, Balantac Z, Crawford A, Ren Y, Toure J, Zchut S, et al. Suppression of the endoplasmic reticulum calcium pump during zebrafish gastrulation affects left-right asymmetry of the heart and brain. Mech Dev. 2008;125:396-410 pubmed publisher..Brain defects include a left-right reversal of pitx2 expression in the dorsal diencephalon and a left-right reversal of the prominent habenular nucleus in the brain...
- Tessadori F, NoÃ«l E, Rens E, Magliozzi R, Evers van Gogh I, Guardavaccaro D, et al. Nodal signaling range is regulated by proprotein convertase-mediated maturation. Dev Cell. 2015;32:631-9 pubmed publisher..Combined in silico and in vivo approaches support a model in which FurinA controls the signaling range of Spaw by cleaving its proprotein into a mature, extracellular form, consequently regulating left-right patterning. ..