Noggin (protein)

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, noggin 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).

NOG
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1M4U
Identifiers
Aliases	NOG, Nog, SYM1, SYNS1, SYNS1A, noggin
External IDs	OMIM: 602991; MGI: 104327; HomoloGene: 3979; GeneCards: NOG; OMA:NOG - orthologs
Gene location (Human) Chr. Chromosome 17 (human) Band 17q22 Start 56,593,699 bp End 56,595,611 bp
Gene location (Mouse) Chr. Chromosome 11 (mouse) Band 11 C|11 54.34 cM Start 89,191,464 bp End 89,193,158 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in retinal pigment epithelium buccal mucosa cell testicle gonad ventricular zone ganglionic eminence decidua canal of the cervix nucleus accumbens stromal cell of endometrium Top expressed in notochord neural groove neural fold ventricular zone phalanx of second toe muscle of thigh embryo embryonic organizer primary visual cortex somite More reference expression data BioGPS n/a
Gene ontology Molecular function protein homodimerization activity protein binding cytokine binding Cellular component extracellular region extracellular space Biological process positive regulation of glomerulus development pattern specification process axial mesoderm development skeletal system development cell differentiation ureteric bud development negative regulation of astrocyte differentiation pituitary gland development positive regulation of branching involved in ureteric bud morphogenesis lung morphogenesis negative regulation of cartilage development somatic stem cell population maintenance fibroblast growth factor receptor signaling pathway involved in neural plate anterior/posterior pattern formation positive regulation of epithelial cell proliferation negative regulation of cytokine activity neural plate morphogenesis negative regulation of cell differentiation anatomical structure formation involved in morphogenesis mesoderm formation negative regulation of apoptotic signaling pathway embryonic digit morphogenesis cellular response to BMP stimulus wound healing in utero embryonic development BMP signaling pathway negative regulation of gene expression somite development negative regulation of osteoblast differentiation embryonic skeletal system development nervous system development axon guidance negative regulation of BMP signaling pathway regulation of BMP signaling pathway multicellular organism development prostatic bud formation limb development central nervous system development cartilage development neural tube closure brain development negative regulation of cell migration notochord morphogenesis cell differentiation in hindbrain mesenchymal cell differentiation regulation of fibroblast growth factor receptor signaling pathway involved in neural plate anterior/posterior pattern formation neural tube development spinal cord development ureteric bud formation epithelial to mesenchymal transition middle ear morphogenesis embryonic skeletal joint morphogenesis urogenital system development endoderm formation negative regulation of cardiac muscle cell proliferation motor neuron axon guidance dorsal/ventral pattern formation negative regulation of canonical Wnt signaling pathway face morphogenesis positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II osteoblast differentiation membranous septum morphogenesis outflow tract morphogenesis endocardial cushion morphogenesis ventricular compact myocardium morphogenesis endoderm development positive regulation of gene expression atrial cardiac muscle tissue morphogenesis negative regulation of pathway-restricted SMAD protein phosphorylation ventricular septum morphogenesis BMP signaling pathway involved in heart development heart trabecula morphogenesis pharyngeal arch artery morphogenesis negative regulation of epithelial to mesenchymal transition involved in endocardial cushion 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: 56.59 – 56.6 Mb Chr 11: 89.19 – 89.19 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Noggin is an inhibitor of several bone morphogenetic proteins (BMPs): it inhibits at least BMP2, 4, 5, 6, 7, 13, and 14.

The protein's name, which is a slang English-language word for "head", was coined in reference to its ability to produce embryos with large heads when exposed at high concentrations.

Function

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 4 (BMP4) 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.

Increased plasma levels of Noggin have been observed in obese mice and in patients with a body mass index over 27. Additionally, it has been shown that Noggin depletion in adipose tissue leads to obesity.

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 and in later stages.

Knockout model

A study of a mouse knockout model tracked the extent to which the absence of noggin affected embryological development. The focus of the study was the formation of the ear and its role in conductive hearing loss. The inner ear underwent multiple deformations affecting the cochlear duct, semicircular canals, and otic capsule portions. Noggin's involvement in the malformations was also shown to be indirect, through its interaction with the notochord and neural axis. The kinking of the notochord and disorientation of the body axis results in a caudal shift in the embryonic body plan of the hindbrain. Major signaling molecules from the rhombomere structures in the hindbrain could not properly induce inner ear formation. This reflected noggin's regulating of BMP as the major source of deformation, rather than noggin directly affecting inner ear development.

Specific knockout models have been created using the Cre-lox system. A model knocking out Noggin specifically in adipocytes has allowed to elucidate that Noggin also plays a role in adipose tissue: its depletion in adipocytes causes alterations in the structure of both brown and white adipose tissue, along with brown fat dysfunction (impaired thermogenesis and βべーた-oxidation) that results in dramatic increases of body weight and percent body fat that causes alterations in the lipid profile and in the liver; the effects vary with gender.

Clinical significance

Noggin proteins play a role in germ layer-specific derivation of specialized cells. The formation of neural tissues, the notochord, hair follicles, and eye structures arise from the ectoderm germ layer. Noggin activity in the mesoderm gives way to the formation of cartilage, bone and muscle growth, and in the endoderm noggin is involved in the development of the lungs.

Early craniofacial development is heavily influenced by the presence of noggin, in accordance with its multiple tissue-specific requirements. Noggin influences the formation and growth of the palate, mandible and skull through its interaction with neural crest cells. Mice with a lack of NOG gene are shown to have an outgrowth of the mandible and a cleft palate. Another craniofacial related deformity due to the absence of noggin is conductive hearing loss caused by uncontrolled outgrowth of the cochlear duct and coiling.

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.

Mutations in this gene have been associated with middle ear abnormalities.

Discovery

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 ultraviolet 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.

Further reading

• Polymeropoulos MH, Poush J, Rubenstein JR, Francomano CA (May 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 (May 1998). "Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite". Genes & Development. 12 (10): 1438–52. doi:10.1101/gad.12.10.1438. PMC 316831. PMID 9585504.
• Brunet LJ, McMahon JA, McMahon AP, Harland RM (May 1998). "Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton". Science. 280 (5368): 1455–7. Bibcode:1998Sci...280.1455B. 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 (July 1998). "Localization of a multiple synostoses-syndrome disease gene to chromosome 17q21-22". American Journal of Human Genetics. 63 (1): 120–4. doi:10.1086/301921. PMC 1377242. PMID 9634519.
• Smith WC (January 1999). "TGF beta inhibitors. New and unexpected requirements in vertebrate development". Trends in Genetics. 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 (March 1999). "Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis". Nature Genetics. 21 (3): 302–4. doi:10.1038/6821. PMID 10080184. S2CID 652235.
• Li W, LoTurco JJ (2000). "Noggin is a negative regulator of neuronal differentiation in developing neocortex". Developmental Neuroscience. 22 (1–2): 68–73. doi:10.1159/000017428. PMID 10657699. S2CID 35547875.
• Dixon ME, Armstrong P, Stevens DB, Bamshad M (2002). "Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism". Genetics in Medicine. 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 (September 2001). "Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding". Proceedings of the National Academy of Sciences of the United States of America. 98 (20): 11353–8. Bibcode:2001PNAS...9811353M. doi:10.1073/pnas.201367598. PMC 58733. PMID 11562478.
• Paine-Saunders S, Viviano BL, Economides AN, Saunders S (January 2002). "Heparan sulfate proteoglycans retain Noggin at the cell surface: a potential mechanism for shaping bone morphogenetic protein gradients". The Journal of Biological Chemistry. 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 (December 2001). "Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome". Clinical Genetics. 60 (6): 447–51. doi:10.1034/j.1399-0004.2001.600607.x. PMID 11846737. S2CID 29452724.
• Mangino M, Flex E, Digilio MC, Giannotti A, Dallapiccola B (March 2002). "Identification of a novel NOG gene mutation (P35S) in an Italian family with symphalangism". Human Mutation. 19 (3): 308. doi:10.1002/humu.9016. PMID 11857750. S2CID 22940188.
• Brown DJ, Kim TB, Petty EM, Downs CA, Martin DM, Strouse PJ, Moroi SE, Milunsky JM, Lesperance MM (September 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". American Journal of Human Genetics. 71 (3): 618–24. doi:10.1086/342067. PMC 379196. PMID 12089654.
• Hall AK, Burke RM, Anand M, Dinsio KJ (July 2002). "Activin and bone morphogenetic proteins are present in perinatal sensory neuron target tissues that induce neuropeptides". Journal of Neurobiology. 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 (December 2002). "Structural basis of BMP signalling inhibition by the cystine knot protein Noggin". Nature. 420 (6916): 636–42. Bibcode:2002Natur.420..636G. doi:10.1038/nature01245. PMID 12478285. S2CID 4386654.
• Brown DJ, Kim TB, Petty EM, Downs CA, Martin DM, Strouse PJ, Moroi SE, Gebarski SS, Lesperance MM (March 2003). "Characterization of a stapes ankylosis family with a NOG mutation". Otology & Neurotology. 24 (2): 210–5. doi:10.1097/00129492-200303000-00014. PMID 12621334. S2CID 26445733.

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.