PDB rendering based on 1m4u.
|Symbols||; SYM1; SYNS1|
Noggin, also known as NOG, is a protein that is involved in the development of many body tissues, including nerve tissue, muscles, and bones. In humans is encoded by the NOG gene. The amino acid sequence of human noggin is highly homologous to that of rat, mouse, and Xenopus (an aquatic-frog genus).
The protein's name, which is a slang American word for "head," was coined in reference to its ability to produce embryos with large heads when exposed at high concentrations.
Noggin is a signaling molecule that plays an important role in promoting somite patterning in the developing embryo. It is released from the notochord and regulates bone morphogenic protein during development. The absence of BMP4 will cause the patterning of the neural tube and somites from the neural plate in the developing embryo. It also causes formation of the head and other dorsal structures.
Noggin function is required for correct nervous system, somite, and skeletal development. Experiments in mice have shown that noggin also plays a role in learning, cognition, bone development, and neural tube fusion. Heterozygous missense mutations in the noggin gene can cause deformities such as joint fusions and syndromes such as multiple synostosis syndrome (SYNS1) and proximal symphalangism (SIM1). SYNS1 is different from SYM1 by causing hip and vertebral fusions. The embryo may also develop shorter bones, miss any skeletal elements, or lack multiple articulating joints.
Noggin is essential for proper bone and limb development, and it carries out many processes that are essential for proper neural development in the embryo.
Mechanism of action
The secreted polypeptide noggin, encoded by the NOG gene, binds and inactivates members of the transforming growth factor-beta (TGF-beta) superfamily signaling proteins, such as bone morphogenetic protein-4 (BMP4).
By diffusing through extracellular matrices more efficiently than members of the TGF-beta superfamily, noggin may have a principal role in creating morphogenic gradients. Noggin appears to have pleiotropic effects, both early in development as well as in later stages. The results of the mouse knockout of noggin suggest that it is involved in numerous developmental processes, such as neural tube fusion and joint formation.
Recently, several heterozygous missense human NOG mutations in unrelated families with proximal symphalangism (SYM1) and multiple synostoses syndrome (SYNS1) have been identified; both SYM1 and SYNS1 have multiple joint fusion as their principal feature, and map to the same region on chromosome 17 (17q22) as NOG. These mutations indicate functional haploinsufficiency where the homozygous forms are embryonically lethal.
All these NOG mutations have altered evolutionarily conserved amino acid residues.
Noggin was originally isolated from the aquatic-frog genus Xenopus. The discovery was based on the organism's ability to restore normal dorsal-ventral body axis in embryos that had been artificially ventralized by UV treatment. Noggin was discovered in the laboratory of Richard M. Harland and William C. Smith at the University of California, Berkeley because of this ability to induce secondary axis formation in frog embryos.
- "Entrez Gene: NOG noggin".
- Oppenheimer SB (1995). "The Discovery of Noggin". The American Biology Teacher 57 (5): 264. doi:10.2307/4449989. JSTOR 4449989.
- Hirsinger E, Duprez D, Jouve C, Malapert P, Cooke J, Pourquié O (1997). "Noggin acts downstream of Wnt and Sonic Hedgehog to antagonize BMP4 in avian somite patterning". Development 124 (22): 4605–14. PMID 9409677.
- Marcelino J, Sciortino CM, Romero MF, Ulatowski LM, Ballock RT, Economides AN, Eimon PM, Harland RM, Warman ML (2001). "Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding". Proc. Natl. Acad. Sci. U.S.A. 98 (20): 11353–8. doi:10.1073/pnas.201367598. PMC 58733. PMID 11562478.
- Krause C, Guzman A, Knaus P (April 2011). "Noggin". Int. J. Biochem. Cell Biol. 43 (4): 478–81. doi:10.1016/j.biocel.2011.01.007. PMID 21256973.
- Valenzuela DM, Economides AN, Rojas E, Lamb TM, Nuñez L, Jones P, Lp NY, Espinosa R, Brannan CI, Gilbert DJ (September 1995). "Identification of mammalian noggin and its expression in the adult nervous system". J. Neurosci. 15 (9): 6077–84. PMID 7666191.
- Polymeropoulos MH, Poush J, Rubenstein JR, Francomano CA (1995). "Localization of the gene (SYM1) for proximal symphalangism to human chromosome 17q21-q22.". Genomics 27 (2): 225–9. doi:10.1006/geno.1995.1035. PMID 7557985.
- McMahon JA, Takada S, Zimmerman LB, Fan CM, Harland RM, McMahon AP (1998). "Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite.". Genes Dev. 12 (10): 1438–52. doi:10.1101/gad.12.10.1438. PMC 316831. PMID 9585504.
- Brunet LJ, McMahon JA, McMahon AP, Harland RM (1998). "Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton.". Science 280 (5368): 1455–7. doi:10.1126/science.280.5368.1455. PMID 9603738.
- Krakow D, Reinker K, Powell B, Cantor R, Priore MA, Garber A, Lachman RS, Rimoin DL, Cohn DH (1998). "Localization of a multiple synostoses-syndrome disease gene to chromosome 17q21-22.". Am. J. Hum. Genet. 63 (1): 120–4. doi:10.1086/301921. PMC 1377242. PMID 9634519.
- Smith WC (1999). "TGF beta inhibitors. New and unexpected requirements in vertebrate development.". Trends Genet. 15 (1): 3–5. doi:10.1016/S0168-9525(98)01641-2. PMID 10087923.
- Gong Y, Krakow D, Marcelino J, Wilkin D, Chitayat D, Babul-Hirji R, Hudgins L, Cremers CW, Cremers FP, Brunner HG, Reinker K, Rimoin DL, Cohn DH, Goodman FR, Reardon W, Patton M, Francomano CA, Warman ML (1999). "Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis.". Nat. Genet. 21 (3): 302–4. doi:10.1038/6821. PMID 10080184.
- Li W, LoTurco JJ (2000). "Noggin is a negative regulator of neuronal differentiation in developing neocortex.". Dev. Neurosci. 22 (1-2): 68–73. doi:10.1159/000017428. PMID 10657699.
- Dixon ME, Armstrong P, Stevens DB, Bamshad M (2002). "Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism.". Genet. Med. 3 (5): 349–53. doi:10.1097/00125817-200109000-00004. PMID 11545688.
- Marcelino J, Sciortino CM, Romero MF, Ulatowski LM, Ballock RT, Economides AN, Eimon PM, Harland RM, Warman ML (2001). "Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding.". Proc. Natl. Acad. Sci. U.S.A. 98 (20): 11353–8. doi:10.1073/pnas.201367598. PMC 58733. PMID 11562478.
- Paine-Saunders S, Viviano BL, Economides AN, Saunders S (2002). "Heparan sulfate proteoglycans retain Noggin at the cell surface: a potential mechanism for shaping bone morphogenetic protein gradients.". J. Biol. Chem. 277 (3): 2089–96. doi:10.1074/jbc.M109151200. PMID 11706034.
- Takahashi T, Takahashi I, Komatsu M, Sawaishi Y, Higashi K, Nishimura G, Saito H, Takada G (2002). "Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome.". Clin. Genet. 60 (6): 447–51. doi:10.1034/j.1399-0004.2001.600607.x. PMID 11846737.
- Mangino M, Flex E, Digilio MC, Giannotti A, Dallapiccola B (2002). "Identification of a novel NOG gene mutation (P35S) in an Italian family with symphalangism.". Hum. Mutat. 19 (3): 308. doi:10.1002/humu.9016. PMID 11857750.
- Brown DJ, Kim TB, Petty EM, Downs CA, Martin DM, Strouse PJ, Moroi SE, Milunsky JM, Lesperance MM (2002). "Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin.". Am. J. Hum. Genet. 71 (3): 618–24. doi:10.1086/342067. PMC 379196. PMID 12089654.
- Hall AK, Burke RM, Anand M, Dinsio KJ (2002). "Activin and bone morphogenetic proteins are present in perinatal sensory neuron target tissues that induce neuropeptides.". J. Neurobiol. 52 (1): 52–60. doi:10.1002/neu.10068. PMID 12115893.
- Groppe J, Greenwald J, Wiater E, Rodriguez-Leon J, Economides AN, Kwiatkowski W, Affolter M, Vale WW, Izpisua Belmonte JC, Choe S (2003). "Structural basis of BMP signalling inhibition by the cystine knot protein Noggin.". Nature 420 (6916): 636–42. doi:10.1038/nature01245. PMID 12478285.
- Brown DJ, Kim TB, Petty EM, Downs CA, Martin DM, Strouse PJ, Moroi SE, Gebarski SS, Lesperance MM (2003). "Characterization of a stapes ankylosis family with a NOG mutation.". Otol. Neurotol. 24 (2): 210–5. doi:10.1097/00129492-200303000-00014. PMID 12621334.
- BMPedia - the Bone Morphogenetic Protein Wiki
- Noggin publications, gene expression data, sequences and interactants from Xenbase
- NOG human gene location in the UCSC Genome Browser.
- NOG human gene details in the UCSC Genome Browser.