Noggin (protein)

Noggin
PDB rendering based on 1m4u.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1M4U
Identifiers
Symbols	NOG; SYM1; SYNS1
External IDs	OMIM: 602991 MGI: 104327 HomoloGene: 3979 GeneCards: NOG Gene
Gene Ontology Molecular function • cytokine binding • protein homodimerization activity Cellular component • extracellular region • extracellular space Biological process • negative regulation of transcription from RNA polymerase II promoter • skeletal system development • osteoblast differentiation • in utero embryonic development • endoderm formation • mesoderm formation • epithelial to mesenchymal transition • neural plate morphogenesis • neural tube closure • nervous system development • motor neuron axon guidance • dorsal/ventral pattern formation • spinal cord development • cell differentiation in hindbrain • pituitary gland development • negative regulation of cell migration • BMP signaling pathway • negative regulation of BMP signaling pathway • somatic stem cell maintenance • wound healing • middle ear morphogenesis • embryonic digit morphogenesis • negative regulation of apoptotic process • negative regulation of osteoblast differentiation • positive regulation of transcription from RNA polymerase II promoter • axial mesoderm development • notochord morphogenesis • embryonic skeletal system development • negative regulation of astrocyte differentiation • positive regulation of epithelial cell proliferation • cartilage development • negative regulation of cardiac muscle cell proliferation • limb development • embryonic skeletal joint morphogenesis • negative regulation of cytokine activity • face morphogenesis • negative regulation of pathway-restricted SMAD protein phosphorylation • lung morphogenesis • prostatic bud formation • ureteric bud formation • fibroblast growth factor receptor signaling pathway involved in neural plate anterior/posterior pattern formation • negative regulation of cartilage development • somite development • cellular response to BMP stimulus • negative regulation of canonical Wnt receptor signaling pathway • positive regulation of branching involved in ureteric bud morphogenesis • positive regulation of glomerulus development • regulation of fibroblast growth factor receptor signaling pathway involved in neural plate anterior/posterior pattern formation Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	9241	18121
Ensembl	ENSG00000183691	ENSMUSG00000048616
UniProt	Q13253	P97466
RefSeq (mRNA)	NM_005450	NM_008711
RefSeq (protein)	NP_005441	NP_032737
Location (UCSC)	Chr 17: 54.67 – 54.67 Mb	Chr 11: 89.3 – 89.3 Mb
PubMed search	[1]	[2]

Noggin, also known as NOG, is a protein which in humans is encoded by the NOG gene.

Noggin inhibits TGF-β signal transduction by binding to TGF-β family ligands and preventing them from binding to their corresponding receptors. Noggin plays a key role in neural induction by inhibiting BMP4, along with other TGF-β signaling inhibitors such as chordin and follistatin. Mouse knockout experiments have demonstrated that noggin also plays a crucial role in learning, cognition, bone development, joint formation, and neural tube fusion.

Genomics

Noggin was originally isolated from Xenopus based on its ability to restore normal dorsal-ventral body axis in embryos that had been artificially ventralized by UV treatment.

The amino acid sequence of human noggin is highly homologous to that of Xenopus, rat and mouse.

Molecular biology

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 effect, 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.

Clinical

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.

Discovery

Noggin was discovered in the laboratory of Richard M. Harland and William C. Smith at the University of California, Berkeley because of its ability to induce secondary axis formation in frog embryos.

Further reading

• 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. 
• Valenzuela DM, Economides AN, Rojas E, et al. (1995). "Identification of mammalian noggin and its expression in the adult nervous system.". J. Neurosci. 15 (9): 6077–84. PMID 7666191. 
• McMahon JA, Takada S, Zimmerman LB, et al. (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, et al. (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, et al. (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, et al. (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. 
• Beck HN, Drahushuk K, Jacoby DB, et al. (2003). "Bone morphogenetic protein-5 (BMP-5) promotes dendritic growth in cultured sympathetic neurons.". BMC neuroscience 2: 12. doi:10.1186/1471-2202-2-12. PMC 56999. PMID 11580864. 
• 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, et al. (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, et al. (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, et al. (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. 
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. 
• Groppe J, Greenwald J, Wiater E, et al. (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, et al. (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. 

External links

• 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.