Role of the Bicoid-related homeodomain factor Pitx1 in specifying hindlimb morphogenesis and pituitary development
Open accessAbstract
Pitx1 is a Bicoid-related homeodomain factor that exhibits preferential expression in the hindlimb, as well as expression in the developing anterior pituitary gland and first branchial arch. Here, we report that Pitx1 gene-deleted mice exhibit striking abnormalities in morphogenesis and growth of the hindlimb, resulting in a limb that exhibits structural changes in tibia and fibula as well as patterning alterations in patella and proximal tarsus, to more closely resemble the corresponding forelimb structures. Deletion of the Pitx1 locus results in decreased distal expression of the hindlimb-specific marker, the T-box factor, Tbx4. On the basis of similar expression patterns in chick, targeted misexpression of chick Pitx1 in the developing wing bud causes the resulting limb to assume altered digit number and morphogenesis, with Tbx4 induction. We hypothesize that Pitx1 serves to critically modulate morphogenesis, growth, and potential patterning of a specific hindlimb region, serving as a component of the morphological and growth distinctions in forelimb and hindlimb identity. Pitx1 gene-deleted mice also exhibit reciprocal abnormalities of two ventral and one dorsal anterior pituitary cell types, presumably on the basis of its synergistic functions with other transcription factors, and defects in the derivatives of the first branchial arch, including cleft palate, suggesting a proliferative defect in these organs analogous to that observed in the hindlimb.
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In amniotes, pitx1 operates in the patterning system for hind limb appendage subparts, and forced expression in forelimb buds transforms them into hindlimbs.
“In amniotes pitx1 operates in the patterning system that organizes the subparts of the appendages developing from the hind limb buds, and forced expression in forelimb buds transforms them into hindlimbs (Logan and Tabin, 1999; Szeto et al., 1999).”
From Evolution of Gene Regulatory Networks Controlling Body Plan Development (2011) · cites this paper as Szeto et al., 1999
The Discussion supports a role for Pitx1 in hindlimb-specific patterning and morphogenesis. But the Effects of cPitx1 misexpression section reports only leg-like changes in infected chick wings, mainly in their distal parts; it does not report that the forelimb buds transform into hindlimbs. Page numbers are unavailable in our copy. (LLM, conf=0.90)
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Cites
A series of normal stages in the development of the chick embryo
Hamburger, V., & Hamilton, H. L. (1951) · Journal of Morphology · doi:10.1002/jmor.1050880104 · Cited by 12,254 · see citing works
Hox genes in vertebrate development
Krumlauf, R. K. (1994) · Cell · doi:10.1016/0092-8674(94)90290-9 · Cited by 2,048 · see citing works
Regulation of Rate of Cartilage Differentiation by Indian Hedgehog and PTH-Related Protein
Vortkamp, A., Lee, K., Lanske, B., Segre, G. V., Kronenberg, H. M., & Tabin, C. J. (1996) · Science · doi:10.1126/science.273.5275.613 · Cited by 1,999 · see citing works
PTH/PTHrP Receptor in Early Development and Indian Hedgehog—Regulated Bone Growth
Lanske, B., Karaplis, A. C., Lee, K., Luz, A., Vortkamp, A., Pirro, A. E., Karperien, M., Defize, L. H. K., Ho, C., Mulligan, R. C., et al. (1996) · Science · doi:10.1126/science.273.5275.663 · Cited by 1,325 · see citing works
Romer, A. S. (1971) · Andalas University Repository (Andalas University) · Cited by 981 · see citing works
Semina, E. V., Reiter, R. S., Leysens, N. J., Alward, W. L. M., Small, K. W., Datson, N. A., Siegel‐Bartelt, J., BIERKE‐NELSON, D., Bitoun, P., Zabel, B., et al. (1996) · Nature Genetics · doi:10.1038/ng1296-392 · Cited by 876 · see citing works
Simmons, D. M., Arriza, J. L., & Swanson, L. W. (1989) · Journal of Histotechnology · doi:10.1179/his.1989.12.3.169 · Cited by 872 · see citing works
Molecular nature of Spemann's organizer: the role of the Xenopus homeobox gene goosecoid
Cho, K. W. Y., Blumberg, B., Steinbeißer, H., & Robertis, E. M. D. (1991) · Cell · doi:10.1016/0092-8674(91)90288-a · Cited by 807 · see citing works
Gehring, W. J., Qian, Y., Billeter, M., Furukubo-Tokunaga, K., Schier, A. F., Reséndez‐Pérez, D., Affolter, M., Otting, G., & Kurt Wüthrich, A. (1994) · Cell · doi:10.1016/0092-8674(94)90292-5 · Cited by 799 · see citing works
Nested expression domains of four homeobox genes in developing rostral brain
Simeone, A., Acampora, D., Gulisano, M., Stornaiuolo, A., & Boncinelli, E. (1992) · Nature · doi:10.1038/358687a0 · Cited by 793 · see citing works
Sornson, M. W., Wu, W., Dasen, J. S., Flynn, S. E., Norman, D. J., O’Connell, S. M., Gukovsky, I., Carrière, C., Ryan, A. K., Miller, A. P., et al. (1996) · Nature · doi:10.1038/384327a0 · Cited by 786 · see citing works
Self-citationAcampora, D., Mazan, S., Lallemand, Y., Avantaggiato, V., Maury, M., Simeone, A., & Brûlet, P. (1995) · Development · doi:10.1242/dev.121.10.3279 · Cited by 702 · see citing works
The roles of FGFs in the early development of vertebrate limbs.Preprint
Martin, G. (1998) · Genes & Development · doi:10.1101/gad.12.11.1571 · Cited by 676 · see citing works
Simeone, A., Acampora, D., Mallamaci, A., Stornaiuolo, A., D’Apice, M. R., Nigro, V., & Boncinelli, E. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb05935.x · Cited by 616 · see citing works
Dollé, P., Izpisúa‐Belmonte, J. C., Falkenstein, H., Renucci, A., & Duboule, D. (1989) · Nature · doi:10.1038/342767a0 · Cited by 608 · see citing works
Molecular Models for Vertebrate Limb Development
Johnson, R. L., & Tabin, C. J. (1997) · Cell · doi:10.1016/s0092-8674(00)80364-5 · Cited by 584 · see citing works
lefty-1 Is Required for Left-Right Determination as a Regulator of lefty-2 and nodal
Meno, C., Shimono, A., Saijoh, Y., Yashiro, K., Mochida, K., Oh‐ishi, S., Noji, S., Kondoh, H., & Hamada, H. (1998) · Cell · doi:10.1016/s0092-8674(00)81472-5 · Cited by 537 · see citing works
Pitx2 determines left–right asymmetry of internal organs in vertebrates
Ryan, A. K., Blumberg, B., Rodrı́guez-Esteban, C., Yonei‐Tamura, S., Tamura, K., Tsukui, T., Peña, J. D. L., Sabbagh, W., Greenwald, J., Choe, S., et al. (1998) · Nature · doi:10.1038/29004 · Cited by 533 · see citing works
Self-citationAng, S., Jin, O., Rhinn, M., Daigle, N., Stevenson, L., & Rossant, J. (1996) · Development · doi:10.1242/dev.122.1.243 · Cited by 501 · see citing works
Multistep signaling requirements for pituitary organogenesis in vivoPreprint
Treier, M., Gleiberman, A. S., O’Connell, S. M., Szeto, D. P., McMahon, J. A., McMahon, A. P., & Rosenfeld, M. G. (1998) · Genes & Development · doi:10.1101/gad.12.11.1691 · Cited by 495 · see citing works
Self-citationAnalysis of Hox gene expression in the chick limb bud
Nelson, C. E., Morgan, B. A., Burke, A. C., Laufer, E., DiMambro, E., Murtaugh, L. C., Gonzales, E., Tessarollo, L., Parada, L. F., & Tabin, C. J. (1996) · Development · doi:10.1242/dev.122.5.1449 · Cited by 481 · see citing works
Logan, M. P. O., Pagán-Westphal, S. M., Smith, D. M., Paganessi, L. A., & Tabin, C. J. (1998) · Cell · doi:10.1016/s0092-8674(00)81474-9 · Cited by 455 · see citing works
Lamonerie, T., Tremblay, J., Lanctôt, C., Therrien, M., Gauthier, Y., & Drouin, J. (1996) · Genes & Development · doi:10.1101/gad.10.10.1284 · Cited by 421 · see citing works
Ericson, J., Norlin, S., Jessell, T. M., & Edlund, H. (1998) · Development · doi:10.1242/dev.125.6.1005 · Cited by 395 · see citing works
Expression of the homeobox Hox-4 genes and the specification of position in chick wing development
Izpisúa‐Belmonte, J. C., Tickle, C. A., Dollé, P., et al. (1991) · Nature · doi:10.1038/350585a0 · Cited by 385 · see citing works
Yoshioka, H., Meno, C., Koshiba, K., Sugihara, M., Itoh, H., Ishimaru, Y., Inoue, T., Ohuchi, H., Semina, E. V., Murray, J. C., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)81473-7 · Cited by 369 · see citing works
Pitx2 Participates in the Late Phase of the Pathway Controlling Left-Right Asymmetry
Piedra, M., Icardo, J. M., Albajar, M., Rodríguez-Rey, J. C., & Ros, M. A. (1998) · Cell · doi:10.1016/s0092-8674(00)81475-0 · Cited by 336 · see citing works
Formation of Rathke’s pouch requires dual induction from the diencephalon
Takuma, N., SHENG, H. Z., Furuta, Y., Ward, J. M., Sharma, K., Hogan, B. L. M., Pfaff, S. L., Westphal, H., Kimura, S., & Mahon, K. A. (1998) · Development · doi:10.1242/dev.125.23.4835 · Cited by 328 · see citing works
Homeobox gene expression correlated with the bifurcation process of limb cartilage development
Yokouchi, Y., Sasaki, H., & Kuroiwa, A. (1991) · Nature · doi:10.1038/353443a0 · Cited by 315 · see citing works
Tremblay, J., Lanctôt, C., & Drouin, J. (1998) · Molecular Endocrinology · doi:10.1210/mend.12.3.0073 · Cited by 315 · see citing works
Gibson-Brown, J., Agulnik, S., Chapman, D. L., Alexiou, M., Garvey, N., Lee, S., & Papaioannou, V. (1996) · Mechanisms of Development · doi:10.1016/0925-4773(96)00514-x · Cited by 288 · see citing works
Epilepsy and brain abnormalities in mice lacking the Otx1 gene
Acampora, D., Mazan, S., Avantaggiato, V., Barone, P., Tuorto, F., Lallemand, Y., Brûlet, P., & Simeone, A. (1996) · Nature Genetics · doi:10.1038/ng1096-218 · Cited by 280 · see citing works
Rhinn, M., Dierich, A., Shawlot, W., Behringer, R. R., LeMeur, M., & Ang, S. (1998) · Development · doi:10.1242/dev.125.5.845 · Cited by 279 · see citing works
Li, H.-S., Tierney, C., Wen, L., Wu, J. Y., & Rao, Y. (1997) · Development · doi:10.1242/dev.124.3.603 · Cited by 276 · see citing works
P-OTX: a PIT-1-interacting homeodomain factor expressed during anterior pituitary gland development.
Szeto, D. P., Ryan, A. K., O’Connell, S. M., & Rosenfeld, M. G. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.15.7706 · Cited by 265 · see citing works
Self-citationBermingham, J. R., Scherer, S. S., O’Connell, S. M., et al. (1996) · Genes & Development · doi:10.1101/gad.10.14.1751 · Cited by 262 · see citing works
Self-citationGage, P. J., & Camper, S. A. (1997) · Human Molecular Genetics · doi:10.1093/hmg/6.3.457 · Cited by 235 · see citing works
Lanctôt, C., Lamolet, B., & Drouin, J. (1997) · Development · doi:10.1242/dev.124.14.2807 · Cited by 220 · see citing works
PARALOGOUS <i>HOX</i> GENES: Function and Regulation
Maconochie, M., Nonchev, S., Morrison, A., & Krumlauf, R. (1996) · Annual Review of Genetics · doi:10.1146/annurev.genet.30.1.529 · Cited by 220 · see citing works
Lin, S., Li, S., Drolet, D. W., & Rosenfeld, M. G. (1994) · Development · doi:10.1242/dev.120.3.515 · Cited by 184 · see citing works
Self-citationInvolvement of T-box genes Tbx2-Tbx5 in vertebrate limb specification and development
Gibson‐Brown, J. J., Agulnik, S. I., Silver, L. M., Niswander, L. A., & Papaioannou, V. E. (1998) · Development · doi:10.1242/dev.125.13.2499 · Cited by 177 · see citing works
Logan, M. P. O., Simon, H., & Tabin, C. (1998) · Development · doi:10.1242/dev.125.15.2825 · Cited by 176 · see citing works
Tbx genes and limb identity in chick embryo development
Isaac, A., Rodrı́guez-Esteban, C., Ryan, A. K., Altabef, M., Tsukui, T., Patel, K., Tickle, C. A., & Izpisúa‐Belmonte, J. C. (1998) · Development · doi:10.1242/dev.125.10.1867 · Cited by 151 · see citing works
Self-citationOhuchi, H., Takeuchi, J., Yoshioka, H., Ishimaru, Y., Ogura, K., Takahashi, N., Ogura, T., & Noji, S. (1998) · Development · doi:10.1242/dev.125.1.51 · Cited by 122 · see citing works
Mandibulo-facial Dysostosis (Treacher Collins Syndrome)
McKenzie, J., & Craig, J. (1955) · Archives of Disease in Childhood · doi:10.1136/adc.30.152.391 · Cited by 117 · see citing works
Fazen, L. E. (1967) · American journal of diseases of children · doi:10.1001/archpedi.1967.02090190051001 · Cited by 115 · see citing works
Kuratani, S., Matsuo, I., & Aizawa, S. (1997) · Developmental Dynamics · doi:10.1002/(sici)1097-0177(199706)209:2 · Cited by 113 · see citing works
Amand, T. R. S., Ra, J., Zhang, Y., et al. (1998) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1998.8740 · Cited by 113 · see citing works
Berry-treacher collins syndrome: A review of 200 cases
ROGERS, B. O. (1964) · British Journal of Plastic Surgery · doi:10.1016/s0007-1226(64)80020-5 · Cited by 104 · see citing works
Acampora, D., Mazan, S., Tuorto, F., Avantaggiato, V., Tremblay, J., Lazzaro, D., Carlo, A. D., Mariano, A., Macchia, P. E., Corte, G., et al. (1998) · Development · doi:10.1242/dev.125.7.1229 · Cited by 100 · see citing works
McDonald, M., & Gorski, J. L. (1993) · Journal of Medical Genetics · doi:10.1136/jmg.30.9.779 · Cited by 86 · see citing works
Limbs are moving: where are they going?
Schwabe, J. W. R. (1998) · Trends in Genetics · doi:10.1016/s0168-9525(98)01477-2 · Cited by 64 · see citing works
Gehring, W. J., Yan, Q. Q., BILLETER, M. A., et al. (1995) · World Scientific series in 20th century chemistry · doi:10.1142/9789812795830_0042 · Cited by 38 · see citing works
Human and murine PTX1/Ptx1 gene maps to the region for Treacher Collins Syndrome
Crawford, M. J., Lanctôt, C., Tremblay, J., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Beatty, B., & Drouin, J. (1997) · Mammalian Genome · doi:10.1007/s003359900589 · Cited by 37 · see citing works
Scott, M. P. (1997) · Nature Genetics · doi:10.1038/ng0297-117 · Cited by 34 · see citing works
Mandibulofacial dysostosis (Treacher-Collins syndrome)
Metro, P. S. (1965) · Oral Surgery Oral Medicine Oral Pathology · doi:10.1016/0030-4220(65)90098-8 · Cited by 28 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- McDonald, M.T. and J.L. Gorski. 1993. Nager acrofacial dysos- tosis. J. Med. Genet. 30(9): 779-782.
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Evolution of Gene Regulatory Networks Controlling Body Plan Development
Peter, I. S., & Davidson, E. H. (2011) · Cell · doi:10.1016/j.cell.2011.02.017 · Cited by 417 · see citing works
Depew, M. J., Tucker, A. S., & Sharpe, P. T. (2002) · Mouse Development · doi:10.1016/b978-012597951-1/50023-8 · Cited by 259 · see citing works
Pendleton, A. L., Shen, F., Taravella, A. M., Emery, S., Veeramah, K. R., Boyko, A. R., & Kidd, J. M. (2018) · BMC Biology · doi:10.1186/s12915-018-0535-2 · Cited by 156 · see citing works
Currie, K. W., & Pearson, B. J. (2013) · Development · doi:10.1242/dev.098590 · Cited by 131 · see citing works
A Single Pitx1 Binding Site Is Essential for Activity of the LHβ Promoter in Transgenic Mice
Quirk, C. C., Lozada, K. L., Keri, R. A., & Nilson, J. H. (2001) · Molecular Endocrinology · doi:10.1210/mend.15.5.0628 · Cited by 88 · see citing works
Cole, N. J., Tanaka, M., Prescott, A., & Tickle, C. (2003) · Current Biology · doi:10.1016/j.cub.2003.11.039 · Cited by 74 · see citing works
- Authors
- Szeto, D. P., Rodriguez-Esteban, C., Ryan, A. K., O'Connell, S. M., Liu, F., Kioussi, C., Gleiberman, A. S., Izpisua-Belmonte, J. C., & Rosenfeld, M. G.
- Affiliations
- Salk Institute for Biological Studies (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1999-02-15
- Volume
- 13
- Issue
- 4
- Pages
- 484-494
- ISSN
- 0890-9369 (ISSN-L)
- PMC
- PMC316471
- OpenAlex
- W2167963456
- Cited by
- 426
- References
- 57
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 8 · 2023: 7 · 2022: 9 · 2021: 17 · 2020: 13 · 2019: 14 · 2018: 11 · 2017: 19 · 2016: 14 · 2015: 4 · 2014: 7 · 2013: 14 · 2012: 16
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Consorzio Interuniversitario Biotecnologie
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- PITX1, anterior pituitary development, TBX4, limb growth, cleft palate, first branchial arch, chick wing bud, transcriptional regulation
- MeSH terms
- Homeobox Protein PITX2, Animals, Branchial Region, Chick Embryo, Hindlimb, Immunohistochemistry, Mandible, Morphogenesis, Nuclear Proteins, Pituitary Gland, Transcription Factors, Wings, Animal, Trans-Activators, Gene Deletion, In Situ Hybridization, Mice, Knockout, Homeodomain Proteins, Gene Expression Regulation, Developmental, T-Box Domain Proteins, Drosophila Proteins, Avian Proteins, Mice, Paired Box Transcription Factors
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