Smad4 is required to regulate the fate of cranial neural crest cells
Open accessAbstract
Smad4 is the central mediator for TGF-beta/BMP signals, which are involved in regulating cranial neural crest (CNC) cell formation, migration, proliferation and fate determination. It is unclear whether TGF-beta/BMP signals utilize Smad-dependent or -independent pathways to control the development of CNC cells. To investigate the functional significance of Smad4 in regulating CNC cells, we generated mice with neural crest specific inactivation of the Smad4 gene. Our study shows that Smad4 is not required for the migration of CNC cells, but is required in neural crest cells for the development of the cardiac outflow tract. Smad4 is essential in mediating BMP signaling in the CNC-derived ectomesenchyme during early stages of tooth development because conditional inactivation of Smad4 in neural crest derived cells results in incisor and molar development arrested at the dental lamina stage. Furthermore, Smad-mediated TGF-beta/BMP signaling controls the homeobox gene patterning of oral/aboral and proximal/distal domains within the first branchial arch. At the cellular level, a Smad4-mediated downstream target gene(s) is required for the survival of CNC cells in the proximal domain of the first branchial arch. Smad4 mutant mice show underdevelopment of the first branchial arch and midline fusion defects. Taken together, our data show that TGF-beta/BMP signals rely on Smad-dependent pathways in the ectomesenchyme to mediate epithelial-mesenchymal interactions that control craniofacial organogenesis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A manually curated signature from an extensive literature review validated the cranial identity of the NCSC lines, and clustering by Pearson correlation excluded genotype- or hairpin-specific expression changes.
“As shown in fig. S2A, a manually curated signature from an extensive literature review (23–28) validated the cranial identity of our NCSC lines, while clustering by Pearson correlation excluded the presence of any genotype- or hairpin-specific expression change.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Smad-dependent and Smad-independent pathways in TGF-β family signalling
Derynck, R., & Zhang, Y. E. (2003) · Nature · doi:10.1038/nature02006 · Cited by 5,370 · see citing works
Generalized lacZ expression with the ROSA26 Cre reporter strain
Soriano, P. (1999) · Nature Genetics · doi:10.1038/5007 · Cited by 5,237 · see citing works
Massagué, J. (2000) · Nature Reviews Molecular Cell Biology · doi:10.1038/35043051 · Cited by 1,882 · see citing works
Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis
Chai, Y., Jiang, X., Ito, Y., Bringas, P., Han, J., Rowitch, D. H., Soriano, P. M., McMahon, A. P., & Sucov, H. M. (2000) · Development · doi:10.1242/dev.127.8.1671 · Cited by 1,464 · see citing works
Self-citationDanielian, P. S., Muccino, D. R., Rowitch, D. H., Michael, S. K., & McMahon, A. P. (1998) · Current Biology · doi:10.1016/s0960-9822(07)00562-3 · Cited by 1,295 · see citing works
Patterning the Vertebrate Neuraxis
Lumsden, A., & Krumlauf, R. K. (1996) · Science · doi:10.1126/science.274.5290.1109 · Cited by 1,146 · see citing works
Reiterative signaling and patterning during mammalian tooth morphogenesis
Jernvall, J., & Thesleff, I. (2000) · Mechanisms of Development · doi:10.1016/s0925-4773(99)00322-6 · Cited by 1,101 · see citing works
Vainio, S. J., Karavanova, I. D., Jowett, A. K., & Thesleff, I. (1993) · Cell · doi:10.1016/s0092-8674(05)80083-2 · Cited by 923 · see citing works
Massagué, J., & Gomis, R. R. (2006) · FEBS Letters · doi:10.1016/j.febslet.2006.04.033 · Cited by 719 · see citing works
Signalling networks regulating dental development
Thesleff, I., & Sharpe, P. T. (1997) · Mechanisms of Development · doi:10.1016/s0925-4773(97)00115-9 · Cited by 650 · see citing works
Recent advances in craniofacial morphogenesis
Chai, Y., & Maxson, R. E. (2006) · Developmental Dynamics · doi:10.1002/dvdy.20833 · Cited by 610 · see citing works
Self-citationThe cutting-edge of mammalian development; how the embryo makes teeth
Tucker, A. S., & Sharpe, P. T. (2004) · Nature Reviews Genetics · doi:10.1038/nrg1380 · Cited by 602 · see citing works
Vertebrate Cranial Placodes I. Embryonic Induction
Baker, C. V. H., & Bronner-Fraser, M. E. (2001) · Developmental Biology · doi:10.1006/dbio.2001.0156 · Cited by 589 · see citing works
Mina, M., & Kollar, E. J. (1987) · Archives of Oral Biology · doi:10.1016/0003-9969(87)90055-0 · Cited by 554 · see citing works
Neural Crest and Cardiovascular Patterning
Kirby, M. L., & Waldo, K. L. (1995) · Circulation Research · doi:10.1161/01.res.77.2.211 · Cited by 534 · see citing works
Sirard, C., de la Pompa, J. L., Elia, A., Itié, A., Mirtsos, C., Cheung, A., Hahn, S. A., Wakeham, A. C., Schwartz, L., Kern, S. E., et al. (1998) · Genes & Development · doi:10.1101/gad.12.1.107 · Cited by 503 · see citing works
Transformation of Tooth Type Induced by Inhibition of BMP Signaling
Tucker, A. S., Matthews, K. L., & Sharpe, P. T. (1998) · Science · doi:10.1126/science.282.5391.1136 · Cited by 458 · see citing works
Thesleff, I., Vaahtokari, A., & Partanen, A. (1995) · The International Journal of Developmental Biology · doi:10.1387/ijdb.7626420 · Cited by 436 · see citing works
Couly, G. F., Creuzet, S., Bennaceur, S., Vincent, C., & Douarin, N. M. L. (2002) · Development · doi:10.1242/dev.129.4.1061 · Cited by 417 · see citing works
Two rhombomeres are altered in Hoxa-1 mutant mice
Mark, M. P., Lufkin, T., Vonesch, J., Ruberte, E., Olivo‐Marín, J., Dollé, P., Gorry, P., Lumsden, A., & Chambon, P. (1993) · Development · doi:10.1242/dev.119.2.319 · Cited by 397 · see citing works
Biological mechanisms of tooth movement and craniofacial adaptation
Birkedal‐Hansen, H. (1993) · American Journal of Orthodontics and Dentofacial Orthopedics · doi:10.1016/s0889-5406(05)80410-x · Cited by 360 · see citing works
Grigoriou, M. E., Tucker, A. S., Sharpe, P. T., & Pachnis, V. (1998) · Development · doi:10.1242/dev.125.11.2063 · Cited by 307 · see citing works
The generation of diversity and pattern in animal development
Gurdon, J. B. (1992) · Cell · doi:10.1016/0092-8674(92)90465-o · Cited by 276 · see citing works
Role of Dlx-1 and Dlx-2 genes in patterning of the murine dentition
Thomas, B., Tucker, A. S., Qiu, M., et al. (1997) · Development · doi:10.1242/dev.124.23.4811 · Cited by 271 · see citing works
Targeted mutation of the murine goosecoid gene results in craniofacial defects and neonatal death
Yamada, G., Mansouri, A., Torres, M., Stuart, E. T., Blum, M., Schultz, M., Robertis, E. M. D., & Gruß, P. (1995) · Development · doi:10.1242/dev.121.9.2917 · Cited by 260 · see citing works
Fgf-8 determines rostral-caudal polarity in the first branchial arch
Tucker, A. S., Yamada, G., Grigoriou, M. E., Pachnis, V., & Sharpe, P. T. (1999) · Development · doi:10.1242/dev.126.1.51 · Cited by 238 · see citing works
Molecular Genetics of Tooth Morphogenesis and Patterning: The Right Shape in the Right Place
Tucker, A. S., & Sharpe, P. T. (1999) · Journal of Dental Research · doi:10.1177/00220345990780040201 · Cited by 232 · see citing works
Generation of Smad4/Dpc4 conditional knockout mice
Yang, X. Y., Li, C., Herrera, P. L., & Deng, C. (2002) · genesis · doi:10.1002/gene.10029 · Cited by 231 · see citing works
Self-citationCrump, J. G., Maves, L., Lawson, N. D., Weinstein, B. M., & Kimmel, C. B. (2004) · Development · doi:10.1242/dev.01444 · Cited by 215 · see citing works
Neural crest contribution to mammalian tooth formation
Milétich, I., & Sharpe, P. T. (2004) · Birth Defects Research Part C Embryo Today Reviews · doi:10.1002/bdrc.20012 · Cited by 202 · see citing works
New insights into craniofacial morphogenesis
Helms, J. A., Cordero, D. R., & Tapadia, M. D. (2005) · Development · doi:10.1242/dev.01705 · Cited by 200 · see citing works
Pharyngeal arch patterning in the absence of neural crest
Veitch, E., Begbie, J., Schilling, T. F., Smith, M. M., & Graham, A. (1999) · Current Biology · doi:10.1016/s0960-9822(00)80118-9 · Cited by 195 · see citing works
Stottmann, R. W., Choi, M., Mishina, Y. M., Meyers, E. N., & Klingensmith, J. (2004) · Development · doi:10.1242/dev.01086 · Cited by 186 · see citing works
Ishii, M., Han, J., Yen, H.-Y., Sucov, H. M., Chai, Y., & Maxson, R. E. (2005) · Development · doi:10.1242/dev.02072 · Cited by 183 · see citing works
Self-citationSevere nasal clefting and abnormal embryonic apoptosis in Alx3/Alx4 double mutant mice
Beverdam, A., Brouwer, A., Reijnen, M., Korving, J., & Meijlink, F. (2001) · Development · doi:10.1242/dev.128.20.3975 · Cited by 170 · see citing works
Medea is a Drosophila Smad4 homolog that is differentially required to potentiate DPP responses
Wisotzkey, R. G., Mehra, A., Sutherland, D. J., Dobens, L. L., Liu, X., Dohrmann, C. E., Attisano, L., & Raftery, L. A. (1998) · Development · doi:10.1242/dev.125.8.1433 · Cited by 152 · see citing works
Specification of neural crest cell formation and migration in mouse embryos
Trainor, P. A. (2005) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2005.06.007 · Cited by 142 · see citing works
Subramanian, G., Schwarz, R. E., Higgins, L., McEnroe, G., Chakravarty, S., Dugar, S., & Reiss, M. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0018 · Cited by 138 · see citing works
Stottmann, R. W., Anderson, R. M., & Klingensmith, J. (2001) · Developmental Biology · doi:10.1006/dbio.2001.0479 · Cited by 137 · see citing works
Threshold-specific requirements for Bmp4 in mandibular development
Liu, W., Selever, J., Murali, D., Sun, X., Brugger, S. M., Ma, L., Schwartz, R. J., Maxson, R. E., Furuta, Y., & Martin, J. F. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.04.019 · Cited by 136 · see citing works
Gaunt, S. J., Blum, M., & Robertis, E. M. D. (1993) · Development · doi:10.1242/dev.117.2.769 · Cited by 130 · see citing works
Gavalas, A., Trainor, P. A., Ariza‐McNaughton, L., & Krumlauf, R. K. (2001) · Development · doi:10.1242/dev.128.15.3017 · Cited by 116 · see citing works
Patterning of the hyoid cartilage depends upon signals arising from the ventral foregut endoderm
Ruhin, B., Creuzet, S., Vincent, C., Benouaiche, L., Douarin, N. M. L., & Couly, G. F. (2003) · Developmental Dynamics · doi:10.1002/dvdy.10380 · Cited by 106 · see citing works
Identification of Two Smad4 Proteins in Xenopus
Masuyama, N., Hanafusa, H., Kusakabe, M., Shibuyà, H., & Nishida, E. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.17.12163 · Cited by 96 · see citing works
Howell, M. T., Itoh, F., Pierreux, C. E., Valgeirsdóttir, S., Itoh, S., ten Dijke, P., & Hill, C. S. (1999) · Developmental Biology · doi:10.1006/dbio.1999.9430 · Cited by 92 · see citing works
Goosecoid acts cell autonomously in mesenchyme-derived tissues during craniofacial development
Rivera‐Pérez, J. A., Wakamiya, M., & Behringer, R. R. (1999) · Development · doi:10.1242/dev.126.17.3811 · Cited by 85 · see citing works
Neural Crest is Involved in Development of Abnormal Myocardial Function
Conway, S. J., Godt, R. E., Hatcher, C. J., Leatherbury, L., Zolotouchnikov, V. V., Brotto, M. A. P., Copp, A. J., Kirby, M. L., & Creazzo, T. L. (1997) · Journal of Molecular and Cellular Cardiology · doi:10.1006/jmcc.1997.0499 · Cited by 82 · see citing works
Chai, Y., Ito, Y., & Han, J. (2003) · Critical Reviews in Oral Biology & Medicine · doi:10.1177/154411130301400202 · Cited by 74 · see citing works
Self-citationHaworth, K. E., Healy, C., Morgan, P. J., & Sharpe, P. T. (2004) · Development · doi:10.1242/dev.01337 · Cited by 64 · see citing works
Cranial Nerve Development: Placodal Neurons Ride the Crest
Barlow, L. A. (2002) · Current Biology · doi:10.1016/s0960-9822(02)00734-0 · Cited by 39 · see citing works
Misexpression of Noggin Leads to Septal Defects in the Outflow Tract of the Chick Heart
Allen, S. P., Bogardi, J., Barlow, A. J., Mir, S. A., Qayyum, S. R., Verbeek, F. J., Anderson, R. H., Francis‐West, P. H., Brown, N. A., & Richardson, M. K. (2001) · Developmental Biology · doi:10.1006/dbio.2001.0291 · Cited by 39 · see citing works
Genetic interaction of Gsc and Dkk1 in head morphogenesis of the mouse
Lewis, S. L., Khoo, P., Young, R. A. D., et al. (2006) · Mechanisms of Development · doi:10.1016/j.mod.2006.10.001 · Cited by 35 · see citing works
Expression and function of activin beta A during mouse cardiac cushion tissue formation
Moore, C. S., Mjaatvedt, C. H., & Gearhart, J. D. (1998) · Developmental Dynamics · doi:10.1002/(sici)1097-0177(199808)212:4 · Cited by 32 · see citing works
Barx1 and evolutionary changes in feeding
Milétich, I., Buchner, G., & Sharpe, P. T. (2005) · Journal of Anatomy · doi:10.1111/j.1469-7580.2005.00486.x · Cited by 26 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Lumsden, A., 1984. The neural crest contribution to tooth development. In: Maderson, P.F.A. (Ed.), Developmental and Evolutionary Biology of the Neural Crest. John Wiley and Sons, London, pp. 3-43.
Cited by
Sorted by citations
Zanella, M., Vitriolo, A., Andirko, A., Martins, P. T., Sturm, S., O’Rourke, T., Laugsch, M., Malerba, N., Skaros, A., Trattaro, S., et al. (2019) · Science Advances · doi:10.1126/sciadv.aaw7908 · Cited by 101 · see citing works
Dalcq, J., Pasque, V., Ghaye, A., Larbuisson, A., Motte, P., Martial, J. A., & Muller, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0050140 · Cited by 52 · see citing works
- Authors
- Ko, S. O., Chung, I. H., Xu, X., Oka, S., Zhao, H., Cho, E. S., Deng, C., & Chai, Y.
- Affiliations
- University of Southern California (US)
- Jeonbuk National University (KR)
- Corresponding author
- Chai, Yang
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2007-12
- Volume
- 312
- Issue
- 1
- Pages
- 435-447
- ISSN
- 0012-1606 (ISSN-L)
- PMC
- PMC2704603
- OpenAlex
- W2060693830
- Cited by
- 78
- References
- 54
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 4 · 2023: 4 · 2022: 3 · 2021: 2 · 2020: 5 · 2019: 2 · 2016: 3 · 2015: 4 · 2014: 4 · 2013: 8 · 2012: 8
- FWCI
- 2.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2055 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- March of Dimes Foundation
- National Institutes of Health
- National Institute of Dental and Craniofacial Research (DE 014078, DE012711, R01DE017007, R01DE012711, R37DE012711, R01DE014078)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Craniofacial Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › dental development and anomalies
- Keywords
- SMAD4, cranial neural crest cells, TGF-β/BMP signaling, BMP signaling, neural crest migration, cardiac outflow tract development, tooth development, dental lamina, first branchial arch, epithelial-mesenchymal interactions
- MeSH terms
- Animals, Branchial Region, Cell Movement, Embryo, Mammalian, Epithelium, Fetal Viability, Mesoderm, Myocardium, Neural Crest, Skull, Tooth, Reproducibility of Results, Apoptosis, Cell Lineage, Integrases, Body Patterning, Wnt Proteins, Mice, Fibroblast Growth Factor 8, Smad4 Protein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
