tsg is expressed in paired dorsal stripes reaching only partially to the lateral sides of the embryo. Expression is found in the dorsal ectoderm during germ band extention. There is no expression in the midline in amnioserosal cells [Images]. There is an additional domain of expression in the anterior most cells of the embryo (Mason, 1994).
A long-standing hypothesis posits that morphological changes may be more likely to result from changes in regulation of gene expression than from changes in the protein coding sequences of genes. The expression pattern of the twisted gastrulation (tsg) gene has been compared among five Drosophila species: D. melanogaster, D. simulans, D. subobscura, D. mojavensis, and D. virilis. The tsg gene encodes a secreted protein that is required for the specification of dorsal midline fates in the Drosophila early embryo. Tsg is unlike other secreted growth and differentiation factors in Drosophila in that its expression pattern can be experimentally varied and still result in normal development. Because of this, its regulatory region may be freer to diverge than that of other developmental genes whose misexpression may lead to lethal defects. Thus, the tsg gene may be a good indicator of the frequency and nature of evolutionary changes affecting patterns of gene expression. Over approximately 60 million years (Myr), the tsg gene has retained a dorsal-on/ventral-off pattern and a middorsal region of expression; but there have been marked changes in the middorsal domain of expression as well as the appearance/loss of other domains of expression along the anterior/posterior axis. Changes between closely related species (approximately 2-5 Myr since divergence) that are not reflected among more distantly related species suggest frequent changes in gene expression over evolutionary time. These changes in gene expression may serve as the raw material for eventual evolutionary changes in morphology (Mason, 1998).
tsg is one of seven known zygotic genes that specify the fate of dorsal cells in Drosophila embryos. Mutations in tsg cause at least some of the cells on the dorsal half of the embryo to adopt more ventral cell fates leading to the proposal that tsg participates in establishing, maintaining, or modulating a gradient of dpp. Mutations of tsg only affect the fate of a narrow strip of dorsal midline cells and do not affect dorsal ectoderm cells. However, the pattern of tsg expression is not coincident with the territories affected by tsg mutations. All tsg mutants lack the following midline-derived structures: labrum, labral sense organ, dorsal bridge and dorsal arm of the pharyngeal skeleton and the posterior tuft (Mason, 1994).
The Twisted Gastrulation (Tsg) protein is one of five secreted proteins required to pattern the dorsal part of the early Drosophila embryo. Unlike the Decapentaplegic (DPP) protein that is required to pattern the entire dorsal half of the embryo, Tsg is needed only to specify the fate of the dorsal midline cells. The tsg gene was expressed with different promoters to address its mechanism of action and relationship to Dpp. When expressed in a ventral stripe of cells, Tsg protein can diffuse to the dorsalmost cells and can rescue the dorsal midline cells in tsg mutant embryos. Despite elevated levels that exceed those needed for biological activity, there was no change in dorsal midline or lateral cell fates under any conditions tested. It is concluded that Tsg does not modulate an activity gradient of Dpp. Instead, it functions in a permissive rather than instructive role to elaborate cell fates along the dorsal midline after peak levels of Dpp activity have 'primed' cells to respond to Tsg. The interaction between Tsg and Dpp defines a novel type of combinatorial synergism (Mason, 1997).
Blitz, I. L., Cho, K. W. Y. Chang, C. (2003). Twisted gastrulation loss-of-function analyses support its role as a BMP inhibitor during early Xenopus embryogenesis. Development 130: 4975-4988. 12952901
Chang, C., et al. (2001). Twisted gastrulation can function as a BMP antagonist. Nature 410: 483-487. 11260717
Eldar, A., et al. (2002). Robustness of the BMP morphogen gradient in Drosophila embryonic patterning. Nature 419: 304-308. 12239569
Gluecksohn-Schoenheimer, S. and Dunn, L. C. (1945). Sirens, aprosopi and intestinal abnormalities in the house mouse. Anat. Rec. 92: 201-213
Graf, D., et al. (2001). Evolutionary conservation, developmental expression, and genomic mapping of mammalian Twisted gastrulation. Mamm Genome. 12(7): 554-60. 11420619
Hoornbeek, F. K. (1970). A gene producing symmelia in the mouse. Teratology 3: 7-10
Ikeya, M., et al. (2008). Twisted gastrulation mutation suppresses skeletal defect phenotypes in Crossveinless 2 mutant mice. Mech. Dev. 125(9-10): 832-42. PubMed Citation: 18644438
Larraín, J., et al. (2001). Proteolytic cleavage of Chordin as a switch for the dual activities of Twisted gastrulation in BMP signaling. Development 128: 4439-4447. 11714670
Lilja, T., et al. (2003). The CBP coactivator functions both upstream and downstream of Dpp/Screw signaling in the early Drosophila embryo. Dev. Biol. 262: 294-302. 14550792
Little, S. C. and Mullins, M. C. (2004). Twisted gastrulation promotes BMP signaling in zebrafish dorsal-ventral axial patterning. Development 131: 5825-5835. 15525664
Mason, E. D. et al. (1994). Dorsal midline fate in Drosophila embryos requires twisted gastrulation, a gene encoding a secreted protein related to human connective tissue growth factor. Genes Dev. 8: 1489-501. PubMed Citation: 7958834
Mason, E. D., et al. (1997). Combinatorial signaling by Twisted Gastrulation and Decapentaplegic. Mech. Dev. 64(1-2): 61-75. PubMed Citation: 9232597
Mason, E. D. and Marsh, J. L. (1998). Changes in the pattern of twisted gastrulation gene expression among Drosophila species. J. Mol. Evol. 46: 180-7. PubMed Citation: 9452520
Nosaka, T., et al. (2003). Mammalian twisted gastrulation is essential for skeleto-lymphogenesis. Mol. Cell. Biol. 23(8): 2969-80. 12665593
Nunes da Fonseca, R., van der Zee, M. and Roth, S. (2010). Evolution of extracellular Dpp modulators in insects: The roles of tolloid and twisted-gastrulation in dorsoventral patterning of the Tribolium embryo. Dev. Biol. 345(1): 80-93. PubMed Citation: 20510683
Oelgeschlager, M., et al. (2000). The evolutionarily conserved BMP-binding protein Twisted gastrulation promotes BMP signaling. Nature 405: 757-763. PubMed Citation: 10866189
Oelgeschläger, M., et al. (2003). The pro-BMP activity of Twisted gastrulation is independent of BMP binding. Development 130: 4047-4056. 12874126
Ross, J. J., et al. (2001). Twisted gastrulation is a conserved extracellular BMP antagonist. Nature 410: 479-483. 11260716
Sawala, A., Sutcliffe, C. and Ashe, H. L. (2012). Multistep molecular mechanism for bone morphogenetic protein extracellular transport in the Drosophila embryo. Proc. Natl. Acad. Sci. 109(28): 11222-7. PubMed Citation: 22733779
Schmidl, M., et al. (2006). Twisted gastrulation modulates bone morphogenetic protein-induced Collagen II and X expression in chondrocytes in vitro and in vivo. J. Biol. Chem. 281: 31790-31800. Medline abstract: 16905550
Scott, I. C., et al. (2001). Homologues of Twisted gastrulation are extracellular cofactors in antagonism of BMP signaling. Nature 410: 475-478. 11260715
Shimmi, O. and O'Connor, M. B. (2003). Physical properties of Tld, Sog, Tsg and Dpp protein interactions are predicted to help create a sharp boundary in Bmp signals during dorsoventral patterning of the Drosophila embryo. Development 130: 4673-4682. 12925593
Shimmi, O., Umulis, D., Othmer, H. and O'Connor, M. B. (2005). Facilitated transport of a Dpp/Scw heterodimer by Sog/Tsg leads to robust patterning of the Drosophila blastoderm embryo. Cell 120(6):873-86. 15797386
Vilmos, P., Gaudenz, K., Hegedus, Z. and Marsh, J. L. (2001). The Twisted gastrulation family of proteins, together with the IGFBP and CCN families, comprise the TIC superfamily of cysteine rich secreted factors. Mol. Pathol. 54(5): 317-23. 11577174
Xie, J. and Fisher, S. (2005). Twisted gastrulation enhances BMP signaling through chordin dependent and independent mechanisms. Development 132: 383-391. 15604098
Yu, K., et al. (2000). Processing of the Drosophila Sog protein creates a novel BMP inhibitory activity. Development 127: 2143-2154. 10769238
Yu, K., et al. (2004). Cysteine repeat domains and adjacent sequences determine distinct Bone morphogenetic protein modulatory activities of the Drosophila Sog protein. Genetics 166: 1323-1336. 15082551
Zakin, L. and De Robertis, E. M. (2004). Inactivation of mouse Twisted gastrulation reveals its role in promoting Bmp4 activity during forebrain development. Development 131(2): 413-24. 14681194
Zakin, L., Reversade, B., Kuroda, H., Lyons, K. M. and De Robertis, E. M. (2005). Sirenomelia in Bmp7 and Tsg compound mutant mice: requirement for Bmp signaling in the development of ventral posterior mesoderm. Development 132(10): 2489-99. 15843411
Zhu, R., Santat, L. A., Markson, J. S., Nandagopal, N., Gregrowicz, J. and Elowitz, M. B. (2023). Reconstitution of morphogen shuttling circuits. Sci Adv 9(28): eadf9336. PubMed ID: 37436981
date revised: 1 June 2024
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