{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T07:57:28Z","timestamp":1791187048578,"version":"4.1.0"},"reference-count":51,"publisher":"The Company of Biologists","issue":"25","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2003,12,22]]},"abstract":"<jats:p>Sonic hedgehog (Shh) signaling is essential for sclerotome development in the mouse. Gli2 and Gli3 are thought to be the primary transcriptional mediators of Shh signaling; however, their roles in Shh induction of sclerotomal genes have not been investigated. Using a combination of mutant analysis and in vitro explant assays, we demonstrate that Gli2 and Gli3 are required for Shh-dependent sclerotome induction. Gli2\u2013\/\u2013Gli3\u2013\/\u2013embryos exhibit a severe loss of sclerotomal gene expression, and somitic mesoderm from these embryos cannot activate sclerotomal genes in response to exogenous Shh. We find that one copy of either Gli2 or Gli3is required to mediate Shh induction of sclerotomal markers Pax1 and Pax9 in vivo and in vitro. Although Gli2 is generally considered an activator and Gli3 a repressor, our results also reveal a repressor function for Gli2 and an activator function for Gli3 in the developing somite. To further dissect the function of each Gli, we used adenovirus to overexpress Gli1, Gli2 and Gli3 in presomitic mesoderm explants. We find that each Gli preferentially activates a distinct set of Shh target genes, suggesting that the functions of Shh in patterning,growth and negative feedback are divided preferentially between different Gli proteins in the somite.<\/jats:p>","DOI":"10.1242\/dev.00851","type":"journal-article","created":{"date-parts":[[2003,11,11]],"date-time":"2003-11-11T01:12:52Z","timestamp":1068513172000},"page":"6233-6243","source":"Crossref","is-referenced-by-count":138,"title":["Interplays of Gli2 and Gli3 and their requirement in mediating Shh-dependent sclerotome induction"],"prefix":"10.1242","volume":"130","author":[{"given":"Laura","family":"Buttitta","sequence":"first","affiliation":[{"name":"Department of Embryology, Carnegie Institution of Washington 115 West University Parkway, Baltimore, MD 21210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Mo","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Genetics, University of Toronto and Program in Developmental Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Chung","family":"Hui","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Genetics, University of Toronto and Program in Developmental Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Ming","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Embryology, Carnegie Institution of Washington 115 West University Parkway, Baltimore, MD 21210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042604413439200_REF1","unstructured":"Bai, C. B., Auerbach, W., Lee, J. S., Stephen, D. and Joyner, A. L. (2002). Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development129,4753-4761."},{"key":"2021042604413439200_REF2","unstructured":"Bai, C. B. and Joyner, A. L. (2001). Gli1 can rescue the in vivo function of Gli2. Development128,5161-5172."},{"key":"2021042604413439200_REF3","doi-asserted-by":"crossref","unstructured":"Bell, D. M., Leung, K. K., Wheatley, S. C., Ng, L. J., Zhou, S.,Ling, K. W., Sham, M. H., Koopman, P., Tam, P. P. and Cheah, K. S.(1997). SOX9 directly regulates the type-II collagen gene. Nat. Genet.16,174-178.","DOI":"10.1038\/ng0697-174"},{"key":"2021042604413439200_REF4","doi-asserted-by":"crossref","unstructured":"Bi, W., Deng, J. M., Zhang, Z., Behringer, R. R. and de Crombrugghe, B. (1999). Sox9 is required for cartilage formation. Nat. Genet.22, 85-89.","DOI":"10.1038\/8792"},{"key":"2021042604413439200_REF5","doi-asserted-by":"crossref","unstructured":"Borycki, A. G., Mendham, L. and Emerson, C. P., Jr(1998). Control of somite patterning by Sonic hedgehog and its downstream signal response genes. Development125,777-790.","DOI":"10.1242\/dev.125.4.777"},{"key":"2021042604413439200_REF6","doi-asserted-by":"crossref","unstructured":"Brent, A. E. and Tabin, C. J. (2002). Developmental regulation of somite derivatives: muscle, cartilage and tendon. Curr. Opin. Genet. Dev.12,548-557.","DOI":"10.1016\/S0959-437X(02)00339-8"},{"key":"2021042604413439200_REF7","doi-asserted-by":"crossref","unstructured":"Briscoe, J., Chen, Y., Jessell, T. M. and Struhl, G.(2001). A hedgehog-insensitive form of patched provides evidence for direct long-range morphogen activity of sonic hedgehog in the neural tube. Mol. Cell7,1279-1291.","DOI":"10.1016\/S1097-2765(01)00271-4"},{"key":"2021042604413439200_REF8","doi-asserted-by":"crossref","unstructured":"Buttitta, L., Tanaka, T. S., Chen, A. E., Ko, M. S. and Fan, C. M. (2003). Microarray analysis of somitogenesis reveals novel targets of different WNT signaling pathways in the somitic mesoderm. Dev. Biol.258,91-104.","DOI":"10.1016\/S0012-1606(03)00116-7"},{"key":"2021042604413439200_REF9","doi-asserted-by":"crossref","unstructured":"Chiang, C., Litingtung, Y., Lee, E., Young, K. E., Corden, J. L., Westphal, H. and Beachy, P. A. (1996). Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature383,407-413.","DOI":"10.1038\/383407a0"},{"key":"2021042604413439200_REF10","doi-asserted-by":"crossref","unstructured":"Chuang, P. T. and McMahon, A. P. (1999). Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature397,617-621.","DOI":"10.1038\/17611"},{"key":"2021042604413439200_REF11","doi-asserted-by":"crossref","unstructured":"Dai, P., Akimaru, H., Tanaka, Y., Maekawa, T., Nakafuku, M. and Ishii, S. (1999). Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J. Biol. Chem.274,8143-8152.","DOI":"10.1074\/jbc.274.12.8143"},{"key":"2021042604413439200_REF12","doi-asserted-by":"crossref","unstructured":"Ding, Q., Motoyama, J., Gasca, S., Mo, R., Sasaki, H., Rossant,J. and Hui, C. C. (1998). Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice. Development125,2533-2543.","DOI":"10.1242\/dev.125.14.2533"},{"key":"2021042604413439200_REF13","unstructured":"Dockter, J. L. (2000). Sclerotome induction and differentiation. Curr. Top. Dev. Biol.48, 77-127."},{"key":"2021042604413439200_REF14","doi-asserted-by":"crossref","unstructured":"Fan, C. M. and Tessier-Lavigne, M. (1994). Patterning of mammalian somites by surface ectoderm and notochord: evidence for sclerotome induction by a hedgehog homolog. Cell79,1175-1186.","DOI":"10.1016\/0092-8674(94)90009-4"},{"key":"2021042604413439200_REF15","doi-asserted-by":"crossref","unstructured":"Fan, C. M., Porter, J. A., Chiang, C., Chang, D. T., Beachy, P. A. and Tessier-Lavigne, M. (1995). Long-range sclerotome induction by sonic hedgehog: direct role of the amino-terminal cleavage product and modulation by the cyclic AMP signaling pathway. Cell81,457-465.","DOI":"10.1016\/0092-8674(95)90398-4"},{"key":"2021042604413439200_REF16","unstructured":"Frohman, M. A., Boyle, M. and Martin, G. R.(1990). Isolation of the mouse Hox-2.9 gene; analysis of embryonic expression suggests that positional information along the anterior-posterior axis is specified by mesoderm. Development110,589-607."},{"key":"2021042604413439200_REF17","doi-asserted-by":"crossref","unstructured":"Fu, Q., Jilka, R. L., Manolagas, S. 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H., Kogerman, P., Lindstrom, E., Toftgard, R. and Biesecker, L. G. (1999). GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization. Proc. Natl. Acad. Sci. USA96,2880-2884.","DOI":"10.1073\/pnas.96.6.2880"},{"key":"2021042604413439200_REF46","doi-asserted-by":"crossref","unstructured":"Taipale, J., Chen, J. K., Cooper, M. K., Wang, B., Mann, R. K.,Milenkovic, L., Scott, M. P. and Beachy, P. A. (2000). Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature406,1005-1009.","DOI":"10.1038\/35023008"},{"key":"2021042604413439200_REF47","doi-asserted-by":"crossref","unstructured":"Wijgerde, M., McMahon, J. A., Rule, M. and McMahon, A. P.(2002). A direct requirement for Hedgehog signaling for normal specification of all ventral progenitor domains in the presumptive mammalian spinal cord. 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