{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T13:48:25Z","timestamp":1789912105291,"version":"4.0.1"},"reference-count":45,"publisher":"The Company of Biologists","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2007,4,15]]},"abstract":"<jats:p>The developing limb serves as a paradigm for studying pattern formation and morphogenetic cell death. Here, we show that conditional deletion of N-Myc(Mycn) in the developing mouse limb leads to uniformly small skeletal elements and profound soft-tissue syndactyly. The small skeletal elements are associated with decreased proliferation of limb bud mesenchyme and small cartilaginous condensations, and syndactyly is associated with a complete absence of interdigital cell death. Although Myc family proteins have pro-apoptotic activity, N-Myc is not expressed in interdigital cells undergoing programmed cell death. We provide evidence indicating that the lack of interdigital cell death and associated syndactyly is related to an absence of interdigital cells marked by expression of Fgfr2 and Msx2. Thus, instead of directly regulating interdigital cell death, we propose that N-Myc is required for the proper generation of undifferentiated mesenchymal cells that become localized to interdigital regions and trigger digit separation when eliminated by programmed cell death. Our results provide new insight into mechanisms that control limb development and suggest that defects in the formation of N-Myc-dependent interdigital tissue may be a root cause of common syndromic forms of syndactyly.<\/jats:p>","DOI":"10.1242\/dev.000703","type":"journal-article","created":{"date-parts":[[2007,3,15]],"date-time":"2007-03-15T00:11:19Z","timestamp":1173917479000},"page":"1583-1592","source":"Crossref","is-referenced-by-count":53,"title":["Activities of N-Myc in the developing limb link control of skeletal size with digit separation"],"prefix":"10.1242","volume":"134","author":[{"given":"Sara","family":"Ota","sequence":"first","affiliation":[{"name":"Shriners Hospitals for Children Portland, 3101 SW Sam Jackson Park Road,Portland, OR 97239, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Qiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Shriners Hospitals for Children Portland, 3101 SW Sam Jackson Park Road,Portland, OR 97239, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doug R.","family":"Keene","sequence":"additional","affiliation":[{"name":"Shriners Hospitals for Children Portland, 3101 SW Sam Jackson Park Road,Portland, OR 97239, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Knoepfler","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Human Anatomy, Davis School of Medicine, 3301 Tupper Hall, University of California, Davis, CA 95616, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Hurlin","sequence":"additional","affiliation":[{"name":"Shriners Hospitals for Children Portland, 3101 SW Sam Jackson Park Road,Portland, OR 97239, USA."},{"name":"Department of Cell and Developmental Biology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042612304179200_REF1","doi-asserted-by":"crossref","unstructured":"Ambler, C. A., Nowicki, J. L., Burke, A. C. and Bautch, V. L. (2001). Assembly of trunk and limb blood vessels involves extensive migration and vasculogenesis of somite-derived angioblasts. Dev. Biol. 234,352-364.","DOI":"10.1006\/dbio.2001.0267"},{"key":"2021042612304179200_REF2","doi-asserted-by":"crossref","unstructured":"Archer, C. W., Dowthwaite, G. P. and Francis-West, P.(2003). Development of synovial joints. Birth Defects Res. C Embryo Today69,144-155.","DOI":"10.1002\/bdrc.10015"},{"key":"2021042612304179200_REF3","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":"2021042612304179200_REF4","doi-asserted-by":"crossref","unstructured":"Boulet, A. M., Moon, A. M., Arenkiel, B. R. and Capecchi, M. R. (2004). The roles of Fgf4 and Fgf8 in limb bud initiation and outgrowth. Dev. Biol. 273,361-372.","DOI":"10.1016\/j.ydbio.2004.06.012"},{"key":"2021042612304179200_REF5","doi-asserted-by":"crossref","unstructured":"Brent, A. E., Schweitzer, R. and Tabin, C. J.(2003). A somitic compartment of tendon progenitors. Cell113,235-248.","DOI":"10.1016\/S0092-8674(03)00268-X"},{"key":"2021042612304179200_REF6","doi-asserted-by":"crossref","unstructured":"Capdevila, J., Tsukui, T., Esteban, V., Zappavigna, J. and Belmont, C. I. (1999). Control of vertebrate limb outgrowth by the proximal factor Meis2 and distal antagonism of BMPs by Gremlin. Mol. Cell4,839-849.","DOI":"10.1016\/S1097-2765(00)80393-7"},{"key":"2021042612304179200_REF7","doi-asserted-by":"crossref","unstructured":"Celli, J., van Bokhoven, H. and Brunner, H. G.(2003). Feingold syndrome: clinical review and genetic mapping. Am. J. Med. Genet. 122,294-300.","DOI":"10.1002\/ajmg.a.20471"},{"key":"2021042612304179200_REF8","doi-asserted-by":"crossref","unstructured":"Dahn, R. D. and Fallon, J. F. (2000). Interdigital regulation of digit identity and homeotic transformation by modulated BMP signaling. Science289,438-441.","DOI":"10.1126\/science.289.5478.438"},{"key":"2021042612304179200_REF9","doi-asserted-by":"crossref","unstructured":"Drossopoulou, G., Lewis, K. E., Sanz-Ezquerro, J. J., Nikbakht,N., McMahon, A. P., Hofmann, C. and Tickle, C. (2000). A model for anteroposterior patterning of the vertebrate limb based on sequential long- and short-range Shh signalling and Bmp signalling. Development127,1337-1348.","DOI":"10.1242\/dev.127.7.1337"},{"key":"2021042612304179200_REF10","doi-asserted-by":"crossref","unstructured":"Dudley, A. T., Ros, M. A. and Tabin, C. J.(2002). A re-examination of proximodistal patterning during vertebrate limb development. Nature418,539-544.","DOI":"10.1038\/nature00945"},{"key":"2021042612304179200_REF11","doi-asserted-by":"crossref","unstructured":"Fallon, J. F., Lopez, A., Ros, M. A., Savage, M. P., Olwin, B. B. and Simandl, B. K. (1994). FGF-2: apical ectodermal ridge growth signal for chick limb development. Science264,104-107.","DOI":"10.1126\/science.7908145"},{"key":"2021042612304179200_REF12","doi-asserted-by":"crossref","unstructured":"Guha, U., Gomes, W. A., Kobayashi, T., Pestell, R. G. and Kessler, J. A. (2002). In vivo evidence that BMP signaling is necessary for apoptosis in the mouse limb. Dev. Biol. 249,108-120.","DOI":"10.1006\/dbio.2002.0752"},{"key":"2021042612304179200_REF13","doi-asserted-by":"crossref","unstructured":"Hurle, J. M. and Ganan, Y. (1986). Interdigital tissue chondrogenesis induced by surgical removal of the ectoderm in the embryonic chick leg bud. J. Embryol. Exp. Morphol. 94,231-244.","DOI":"10.1242\/dev.94.1.231"},{"key":"2021042612304179200_REF14","doi-asserted-by":"crossref","unstructured":"Hurlin, P. J. (2005). N-myc functions in transcription and development. Birth Defects Res. 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Nature423,319-325.","DOI":"10.1038\/nature01655"},{"key":"2021042612304179200_REF21","doi-asserted-by":"crossref","unstructured":"Merino, R., Rodriguez-Leon, J., Macias, D., Ganan, Y.,Economides, A. N. and Hurle, J. M. (1999). The BMP antagonist Gremlin regulates outgrowth, chondrogenesis and programmed cell death in the developing limb. Development126,5515-5522.","DOI":"10.1242\/dev.126.23.5515"},{"key":"2021042612304179200_REF22","doi-asserted-by":"crossref","unstructured":"Murphy, M. J., Wilson, A. and Trumpp, A.(2005). More than just proliferation: Myc function in stem cells. Trends Cell Biol. 15,128-137.","DOI":"10.1016\/j.tcb.2005.01.008"},{"key":"2021042612304179200_REF23","doi-asserted-by":"crossref","unstructured":"Nilsson, J. A. and Cleveland, J. L. (2003). Myc pathways provoking cell suicide and cancer. Oncogene22,9007-9021.","DOI":"10.1038\/sj.onc.1207261"},{"key":"2021042612304179200_REF24","doi-asserted-by":"crossref","unstructured":"Niswander, L. (2003). Pattern formation: old models out on a limb. Nat. Rev. Genet. 4, 133-143.","DOI":"10.1038\/nrg1001"},{"key":"2021042612304179200_REF25","doi-asserted-by":"crossref","unstructured":"Okubo, T., Knoepfler, P. S., Eisenman, R. N. and Hogan, B. L. (2005). Nmyc plays an essential role during lung development as a dosage-sensitive regulator of progenitor cell proliferation and differentiation. Development132,1363-1374.","DOI":"10.1242\/dev.01678"},{"key":"2021042612304179200_REF26","unstructured":"Omi, M., Sato-Maeda, M. and Ide, H. (2000). Role of chondrogenic tissue in programmed cell death and BMP expression in chick limb buds. Int. J. Dev. Biol. 44,381-388."},{"key":"2021042612304179200_REF27","doi-asserted-by":"crossref","unstructured":"Paznekas, W. A., Cunningham, M. L., Howard, T. D., Korf, B. R.,Lipsonm, M. H., Grix, A. W., Feingold, M., Goldberg, R., Borochowitz, Z.,Aleck, K. et al. (1998). Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations. Am. J. 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Positional information in chick limb morphogenesis. Nature244,492-496.","DOI":"10.1038\/244492a0"},{"key":"2021042612304179200_REF35","doi-asserted-by":"crossref","unstructured":"Sun, X., Mariani, F. V. and Martin, G. R.(2002). Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature418,501-508.","DOI":"10.1038\/nature00902"},{"key":"2021042612304179200_REF36","doi-asserted-by":"crossref","unstructured":"te Welscher, P., Fernandez-Teran, M., Ros, M. A. and Zeller,R. (2002). Mutual genetic antagonism involving GLI3 and dHAND prepatterns the vertebrate limb bud mesenchyme prior to SHH signaling. Genes Dev. 16,421-426.","DOI":"10.1101\/gad.219202"},{"key":"2021042612304179200_REF37","unstructured":"Temtamy, S. A. and McKusick, V. A. (1978). The genetics of hand malformations. Birth Defects Orig. Artic. Ser. 14,i-xviii, 1-619."},{"key":"2021042612304179200_REF38","doi-asserted-by":"crossref","unstructured":"Tickle, C. (2003). Patterning systems - from one end of the limb to the other. Dev. Cell. 4, 449-458.","DOI":"10.1016\/S1534-5807(03)00095-9"},{"key":"2021042612304179200_REF39","doi-asserted-by":"crossref","unstructured":"van Bokhoven, H., Celli, J., van Reeuwijk, J., Rinne, T.,Glaudemans, B., van Beusekom, E., Rieu, P., Newbury-Ecob, R. A., Chiang, C. and Brunner, H. G. (2005). MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome. Nat. Genet. 37,465-467.","DOI":"10.1038\/ng1546"},{"key":"2021042612304179200_REF40","doi-asserted-by":"crossref","unstructured":"Vargesson, N., Clarke, J. D., Vincent, K., Coles, C., Wolpert,L. and Tickle, C. (1997). Cell fate in the chick limb bud and relationship to gene expression. Development124,1909-1918.","DOI":"10.1242\/dev.124.10.1909"},{"key":"2021042612304179200_REF41","doi-asserted-by":"crossref","unstructured":"Wang, C. K., Omi, M., Ferrari, D., Cheng, H. C., Lizarraga, G.,Chin, H. J., Upholt, W. B., Dealy, C. N. and Kosher, R. A.(2004). Function of BMPs in the apical ectoderm of the developing mouse limb. Dev. Biol. 269,109-122.","DOI":"10.1016\/j.ydbio.2004.01.016"},{"key":"2021042612304179200_REF42","doi-asserted-by":"crossref","unstructured":"Wilkie, A. O., Patey, S. J., Kan, S. H., van den Ouweland, A. M. and Hamel, B. C. (2002). FGFs, their receptors, and human limb malformations: clinical and molecular correlations. Am. J. Med. Genet. 112,266-278.","DOI":"10.1002\/ajmg.10775"},{"key":"2021042612304179200_REF43","doi-asserted-by":"crossref","unstructured":"Zucker, R. M., Hunter, E. S., 3rd and Rogers, J. M.(1999). Apoptosis and morphology in mouse embryos by confocal laser scanning microscopy. Methods18,473-480.","DOI":"10.1006\/meth.1999.0815"},{"key":"2021042612304179200_REF44","doi-asserted-by":"crossref","unstructured":"Zuniga, A., Haramis, A.-P. G., McMahon, A. P. and Zeller, R.(1999). Signal relay by BMP antagonism controls the SHH\/FGF4 feedback loop in vertebrate limb buds. Nature401,598-602.","DOI":"10.1038\/44157"},{"key":"2021042612304179200_REF45","doi-asserted-by":"crossref","unstructured":"Zuzarte-Luis, V. and Hurle, J. M. (2005). Programmed cell death in the embryonic vertebrate limb. Semin. Cell Dev. 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