Noggin (protein): Difference between revisions

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<nowiki> </nowiki>{{Infobox_gene}}
<nowiki> </nowiki>{{Infobox_gene}}
'''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]].<ref name="entrez">{{cite web | title = Entrez Gene: NOG noggin| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9241| accessdate = }}</ref> The amino acid sequence of human noggin is highly homologous to that of [[rat]], [[mouse]], and ''[[Xenopus]] (''an aquatic-frog genus).
'''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]].<ref name="entrez">{{cite web | title = Entrez Gene: NOG noggin| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9241| accessdate = }}</ref> 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 English-language word for "head," was coined in reference to its ability to produce embryos with large heads when exposed at high concentrations.<ref>{{Cite journal | title = The Discovery of Noggin | author = Oppenheimer SB | journal = The American Biology Teacher | year = 1995 | volume = 57 | issue = 5  | doi = 10.2307/4449989 | jstor = 4449989 | pages = 264}}</ref>
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.<ref>{{Cite journal | title = The Discovery of Noggin | author = Oppenheimer SB | journal = The American Biology Teacher | year = 1995 | volume = 57 | issue = 5  | doi = 10.2307/4449989 | jstor = 4449989 | pages = 264| hdl = 10211.2/1126 }}</ref>


== Function ==
== Function ==


Noggin is a signaling molecule that plays an important role in promoting [[somite]] patterning in the developing embryo.<ref name="Hirsinger_1997">{{cite journal | vauthors = Hirsinger E, Duprez D, Jouve C, Malapert P, Cooke J, Pourquié O | title = Noggin acts downstream of Wnt and Sonic Hedgehog to antagonize BMP4 in avian somite patterning | journal = Development | volume = 124 | issue = 22 | pages = 4605–14 | date = Nov 1997 | pmid = 9409677 | doi =  }}</ref>  It is released from the [[notochord]] and regulates [[bone morphogenetic protein 4|bone morphogenic protein]] (BMP4) during development.<ref name="Marcelino_2001">{{cite journal | vauthors = Marcelino J, Sciortino CM, Romero MF, Ulatowski LM, Ballock RT, Economides AN, Eimon PM, Harland RM, Warman ML | title = Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 20 | pages = 11353–8 | date = Sep 2001 | pmid = 11562478 | pmc = 58733 | doi = 10.1073/pnas.201367598 }}</ref> 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.<ref name="Marcelino_2001"/>
Noggin is a signaling molecule that plays an important role in promoting [[somite]] patterning in the developing embryo.<ref name="Hirsinger_1997">{{cite journal | vauthors = Hirsinger E, Duprez D, Jouve C, Malapert P, Cooke J, Pourquié O | title = Noggin acts downstream of Wnt and Sonic Hedgehog to antagonize BMP4 in avian somite patterning | journal = Development | volume = 124 | issue = 22 | pages = 4605–14 | date = November 1997 | pmid = 9409677 | doi =  }}</ref>  It is released from the [[notochord]] and regulates [[bone morphogenetic protein 4|bone morphogenic protein]] (BMP4) during development.<ref name="Marcelino_2001">{{cite journal | vauthors = Marcelino J, Sciortino CM, Romero MF, Ulatowski LM, Ballock RT, Economides AN, Eimon PM, Harland RM, Warman ML | title = Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 20 | pages = 11353–8 | date = September 2001 | pmid = 11562478 | pmc = 58733 | doi = 10.1073/pnas.201367598 }}</ref> 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.<ref name="Marcelino_2001"/>


Noggin function is required for correct nervous system, somite, and skeletal development.<ref name="Marcelino_2001" /> Experiments in mice have shown that noggin also plays a role in learning, cognition, bone development, and neural tube fusion.{{citation needed|date=April 2014}} Heterozygous [[missense mutation]]s in the noggin gene can cause deformities such as joint fusions and syndromes such as multiple [[synostosis]] syndrome (SYNS1) and proximal symphalangism (SIM1).<ref name="Marcelino_2001" /> SYNS1 is different from SYM1 by causing hip and vertebral fusions.<ref name="Marcelino_2001" />  The embryo may also develop shorter bones, miss any skeletal elements, or lack multiple articulating joints.<ref name="Marcelino_2001" />
Noggin function is required for correct nervous system, somite, and skeletal development.<ref name="Marcelino_2001" /> Experiments in mice have shown that noggin also plays a role in learning, cognition,<ref>{{cite journal | vauthors = Xu H, Huang W, Wang Y, Sun W, Tang J, Li D, Xu P, Guo L, Yin ZQ, Fan X | title = The function of BMP4 during neurogenesis in the adult hippocampus in Alzheimer's disease | journal = Ageing Research Reviews | volume = 12 | issue = 1 | pages = 157–64 | date = January 2013 | pmid = 22698853 | doi = 10.1016/j.arr.2012.05.002 }}</ref> bone development,<ref>{{cite journal | vauthors = Potti TA, Petty EM, Lesperance MM | title = A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related-symphalangism spectrum disorder (NOG-SSD) | journal = Human Mutation | volume = 32 | issue = 8 | pages = 877–86 | date = August 2011 | pmid = 21538686 | doi = 10.1002/humu.21515 }}</ref> and neural tube fusion.<ref>{{cite journal | vauthors = Liu A, Niswander LA | title = Bone morphogenetic protein signalling and vertebrate nervous system development | journal = Nature Reviews. Neuroscience | volume = 6 | issue = 12 | pages = 945–54 | date = December 2005 | pmid = 16340955 | doi = 10.1038/nrn1805 }}</ref> Heterozygous [[missense mutation]]s in the noggin gene can cause deformities such as joint fusions and syndromes such as multiple [[synostosis]] syndrome (SYNS1) and proximal symphalangism (SIM1).<ref name="Marcelino_2001" /> SYNS1 is different from SYM1 by causing hip and vertebral fusions.<ref name="Marcelino_2001" />  The embryo may also develop shorter bones, miss any skeletal elements, or lack multiple articulating joints.<ref name="Marcelino_2001" />


== Mechanism of action ==
== Mechanism of action ==
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=== Knockout model ===
=== Knockout model ===


A study of a [[Knockout mouse|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]], [[semilunar canal]], 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.<ref>{{cite journal | vauthors = Bok J, Brunet LJ, Howard O, Burton Q, Wu DK | title = Role of hindbrain in inner ear morphogenesis: analysis of Noggin knockout mice | journal = Developmental Biology | volume = 311 | issue = 1 | pages = 69–78 | date = Nov 2007 | pmid = 17900554 | doi = 10.1016/j.ydbio.2007.08.013 | pmc=2215324}}</ref>
A study of a [[Knockout mouse|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 canal]], 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.<ref>{{cite journal | vauthors = Bok J, Brunet LJ, Howard O, Burton Q, Wu DK | title = Role of hindbrain in inner ear morphogenesis: analysis of Noggin knockout mice | journal = Developmental Biology | volume = 311 | issue = 1 | pages = 69–78 | date = November 2007 | pmid = 17900554 | pmc = 2215324 | doi = 10.1016/j.ydbio.2007.08.013 }}</ref>


== Clinical significance ==
== 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.<ref name="pmid21256973">{{cite journal | vauthors = Krause C, Guzman A, Knaus P | title = Noggin | journal = The International Journal of Biochemistry & Cell Biology | volume = 43 | issue = 4 | pages = 478–81 | date = Apr 2011 | pmid = 21256973 | doi = 10.1016/j.biocel.2011.01.007 }}</ref>
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.<ref name="pmid21256973">{{cite journal | vauthors = Krause C, Guzman A, Knaus P | title = Noggin | journal = The International Journal of Biochemistry & Cell Biology | volume = 43 | issue = 4 | pages = 478–81 | date = April 2011 | pmid = 21256973 | doi = 10.1016/j.biocel.2011.01.007 }}</ref>


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.<ref name=Masuda>{{cite journal | vauthors = Masuda S, Namba K, Mutai H, Usui S, Miyanaga Y, Kaneko H, Matsunaga T | title = A mutation in the heparin-binding site of noggin as a novel mechanism of proximal symphalangism and conductive hearing loss | journal = Biochemical and Biophysical Research Communications | year = 2014 | volume = 447 | issue = 3 | pages = 496–502 | pmid = 24735539 | doi = 10.1016/j.bbrc.2014.04.015 }}</ref>
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.<ref name=Masuda>{{cite journal | vauthors = Masuda S, Namba K, Mutai H, Usui S, Miyanaga Y, Kaneko H, Matsunaga T | title = A mutation in the heparin-binding site of noggin as a novel mechanism of proximal symphalangism and conductive hearing loss | journal = Biochemical and Biophysical Research Communications | volume = 447 | issue = 3 | pages = 496–502 | date = May 2014 | pmid = 24735539 | doi = 10.1016/j.bbrc.2014.04.015 }}</ref>


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.<ref name="pmid21256973"/>
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.<ref name="pmid21256973"/>
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== Discovery ==
== 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|UV]] treatment. Noggin was discovered in the laboratory of [[Richard M. Harland]] and William C. Smith at the [[Uc berkeley|University of California, Berkeley]] because of this ability to induce secondary axis formation in frog embryos.<ref name="pmid7666191">{{cite journal | vauthors = Valenzuela DM, Economides AN, Rojas E, Lamb TM, Nuñez L, Jones P, Lp NY, Espinosa R, Brannan CI, Gilbert DJ | title = Identification of mammalian noggin and its expression in the adult nervous system | journal = The Journal of Neuroscience | volume = 15 | issue = 9 | pages = 6077–84 | date = Sep 1995 | pmid = 7666191 | url = http://www.jneurosci.org/cgi/content/abstract/15/9/6077 }}</ref>
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|UV]] treatment. Noggin was discovered in the laboratory of [[Richard M. Harland]] and William C. Smith at the [[Uc berkeley|University of California, Berkeley]] because of this ability to induce secondary axis formation in frog embryos.<ref name="pmid7666191">{{cite journal | vauthors = Valenzuela DM, Economides AN, Rojas E, Lamb TM, Nuñez L, Jones P, Lp NY, Espinosa R, Brannan CI, Gilbert DJ | title = Identification of mammalian noggin and its expression in the adult nervous system | journal = The Journal of Neuroscience | volume = 15 | issue = 9 | pages = 6077–84 | date = September 1995 | pmid = 7666191 | url = http://www.jneurosci.org/cgi/content/abstract/15/9/6077 }}</ref>


== References ==
== References ==
{{Reflist}}
{{Reflist|32em}}


== Further reading ==
== Further reading ==
{{refbegin | 2}}
{{refbegin|32em}}
* {{cite journal | vauthors = Polymeropoulos MH, Poush J, Rubenstein JR, Francomano CA | title = Localization of the gene (SYM1) for proximal symphalangism to human chromosome 17q21-q22 | journal = Genomics | volume = 27 | issue = 2 | pages = 225–9 | date = May 1995 | pmid = 7557985 | doi = 10.1006/geno.1995.1035 }}
* {{cite journal | vauthors = Polymeropoulos MH, Poush J, Rubenstein JR, Francomano CA | title = Localization of the gene (SYM1) for proximal symphalangism to human chromosome 17q21-q22 | journal = Genomics | volume = 27 | issue = 2 | pages = 225–9 | date = May 1995 | pmid = 7557985 | doi = 10.1006/geno.1995.1035 }}
* {{cite journal | vauthors = McMahon JA, Takada S, Zimmerman LB, Fan CM, Harland RM, McMahon AP | title = Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite | journal = Genes & Development | volume = 12 | issue = 10 | pages = 1438–52 | date = May 1998 | pmid = 9585504 | pmc = 316831 | doi = 10.1101/gad.12.10.1438 }}
* {{cite journal | vauthors = McMahon JA, Takada S, Zimmerman LB, Fan CM, Harland RM, McMahon AP | title = Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite | journal = Genes & Development | volume = 12 | issue = 10 | pages = 1438–52 | date = May 1998 | pmid = 9585504 | pmc = 316831 | doi = 10.1101/gad.12.10.1438 }}
* {{cite journal | vauthors = Brunet LJ, McMahon JA, McMahon AP, Harland RM | title = Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton | journal = Science | volume = 280 | issue = 5368 | pages = 1455–7 | date = May 1998 | pmid = 9603738 | doi = 10.1126/science.280.5368.1455 }}
* {{cite journal | vauthors = Brunet LJ, McMahon JA, McMahon AP, Harland RM | title = Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton | journal = Science | volume = 280 | issue = 5368 | pages = 1455–7 | date = May 1998 | pmid = 9603738 | doi = 10.1126/science.280.5368.1455 }}
* {{cite journal | vauthors = Krakow D, Reinker K, Powell B, Cantor R, Priore MA, Garber A, Lachman RS, Rimoin DL, Cohn DH | title = Localization of a multiple synostoses-syndrome disease gene to chromosome 17q21-22 | journal = American Journal of Human Genetics | volume = 63 | issue = 1 | pages = 120–4 | date = Jul 1998 | pmid = 9634519 | pmc = 1377242 | doi = 10.1086/301921 }}
* {{cite journal | vauthors = Krakow D, Reinker K, Powell B, Cantor R, Priore MA, Garber A, Lachman RS, Rimoin DL, Cohn DH | title = Localization of a multiple synostoses-syndrome disease gene to chromosome 17q21-22 | journal = American Journal of Human Genetics | volume = 63 | issue = 1 | pages = 120–4 | date = July 1998 | pmid = 9634519 | pmc = 1377242 | doi = 10.1086/301921 }}
* {{cite journal | vauthors = Smith WC | title = TGF beta inhibitors. New and unexpected requirements in vertebrate development | journal = Trends in Genetics | volume = 15 | issue = 1 | pages = 3–5 | date = Jan 1999 | pmid = 10087923 | doi = 10.1016/S0168-9525(98)01641-2 }}
* {{cite journal | vauthors = Smith WC | title = TGF beta inhibitors. New and unexpected requirements in vertebrate development | journal = Trends in Genetics | volume = 15 | issue = 1 | pages = 3–5 | date = January 1999 | pmid = 10087923 | doi = 10.1016/S0168-9525(98)01641-2 }}
* {{cite journal | vauthors = 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 | title = Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis | journal = Nature Genetics | volume = 21 | issue = 3 | pages = 302–4 | date = Mar 1999 | pmid = 10080184 | doi = 10.1038/6821 }}
* {{cite journal | vauthors = 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 | title = Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis | journal = Nature Genetics | volume = 21 | issue = 3 | pages = 302–4 | date = March 1999 | pmid = 10080184 | doi = 10.1038/6821 }}
* {{cite journal | vauthors = Li W, LoTurco JJ | title = Noggin is a negative regulator of neuronal differentiation in developing neocortex | journal = Developmental Neuroscience | volume = 22 | issue = 1–2 | pages = 68–73 | year = 2000 | pmid = 10657699 | doi = 10.1159/000017428 }}
* {{cite journal | vauthors = Li W, LoTurco JJ | title = Noggin is a negative regulator of neuronal differentiation in developing neocortex | journal = Developmental Neuroscience | volume = 22 | issue = 1–2 | pages = 68–73 | year = 2000 | pmid = 10657699 | doi = 10.1159/000017428 }}
* {{cite journal | vauthors = Dixon ME, Armstrong P, Stevens DB, Bamshad M | title = Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism | journal = Genetics in Medicine | volume = 3 | issue = 5 | pages = 349–53 | year = 2002 | pmid = 11545688 | doi = 10.1097/00125817-200109000-00004 }}
* {{cite journal | vauthors = Dixon ME, Armstrong P, Stevens DB, Bamshad M | title = Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism | journal = Genetics in Medicine | volume = 3 | issue = 5 | pages = 349–53 | year = 2002 | pmid = 11545688 | doi = 10.1097/00125817-200109000-00004 }}
* {{cite journal | vauthors = Marcelino J, Sciortino CM, Romero MF, Ulatowski LM, Ballock RT, Economides AN, Eimon PM, Harland RM, Warman ML | title = Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 20 | pages = 11353–8 | date = Sep 2001 | pmid = 11562478 | pmc = 58733 | doi = 10.1073/pnas.201367598 }}
* {{cite journal | vauthors = Marcelino J, Sciortino CM, Romero MF, Ulatowski LM, Ballock RT, Economides AN, Eimon PM, Harland RM, Warman ML | title = Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 20 | pages = 11353–8 | date = September 2001 | pmid = 11562478 | pmc = 58733 | doi = 10.1073/pnas.201367598 }}
* {{cite journal | vauthors = Paine-Saunders S, Viviano BL, Economides AN, Saunders S | title = Heparan sulfate proteoglycans retain Noggin at the cell surface: a potential mechanism for shaping bone morphogenetic protein gradients | journal = The Journal of Biological Chemistry | volume = 277 | issue = 3 | pages = 2089–96 | date = Jan 2002 | pmid = 11706034 | doi = 10.1074/jbc.M109151200 }}
* {{cite journal | vauthors = Paine-Saunders S, Viviano BL, Economides AN, Saunders S | title = Heparan sulfate proteoglycans retain Noggin at the cell surface: a potential mechanism for shaping bone morphogenetic protein gradients | journal = The Journal of Biological Chemistry | volume = 277 | issue = 3 | pages = 2089–96 | date = January 2002 | pmid = 11706034 | doi = 10.1074/jbc.M109151200 }}
* {{cite journal | vauthors = Takahashi T, Takahashi I, Komatsu M, Sawaishi Y, Higashi K, Nishimura G, Saito H, Takada G | title = Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome | journal = Clinical Genetics | volume = 60 | issue = 6 | pages = 447–51 | date = Dec 2001 | pmid = 11846737 | doi = 10.1034/j.1399-0004.2001.600607.x }}
* {{cite journal | vauthors = Takahashi T, Takahashi I, Komatsu M, Sawaishi Y, Higashi K, Nishimura G, Saito H, Takada G | title = Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome | journal = Clinical Genetics | volume = 60 | issue = 6 | pages = 447–51 | date = December 2001 | pmid = 11846737 | doi = 10.1034/j.1399-0004.2001.600607.x }}
* {{cite journal | vauthors = Mangino M, Flex E, Digilio MC, Giannotti A, Dallapiccola B | title = Identification of a novel NOG gene mutation (P35S) in an Italian family with symphalangism | journal = Human Mutation | volume = 19 | issue = 3 | pages = 308 | date = Mar 2002 | pmid = 11857750 | doi = 10.1002/humu.9016 }}
* {{cite journal | vauthors = Mangino M, Flex E, Digilio MC, Giannotti A, Dallapiccola B | title = Identification of a novel NOG gene mutation (P35S) in an Italian family with symphalangism | journal = Human Mutation | volume = 19 | issue = 3 | pages = 308 | date = March 2002 | pmid = 11857750 | doi = 10.1002/humu.9016 }}
* {{cite journal | vauthors = Brown DJ, Kim TB, Petty EM, Downs CA, Martin DM, Strouse PJ, Moroi SE, Milunsky JM, Lesperance MM | title = 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 | journal = American Journal of Human Genetics | volume = 71 | issue = 3 | pages = 618–24 | date = Sep 2002 | pmid = 12089654 | pmc = 379196 | doi = 10.1086/342067 }}
* {{cite journal | vauthors = Brown DJ, Kim TB, Petty EM, Downs CA, Martin DM, Strouse PJ, Moroi SE, Milunsky JM, Lesperance MM | title = 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 | journal = American Journal of Human Genetics | volume = 71 | issue = 3 | pages = 618–24 | date = September 2002 | pmid = 12089654 | pmc = 379196 | doi = 10.1086/342067 }}
* {{cite journal | vauthors = Hall AK, Burke RM, Anand M, Dinsio KJ | title = Activin and bone morphogenetic proteins are present in perinatal sensory neuron target tissues that induce neuropeptides | journal = Journal of Neurobiology | volume = 52 | issue = 1 | pages = 52–60 | date = Jul 2002 | pmid = 12115893 | doi = 10.1002/neu.10068 }}
* {{cite journal | vauthors = Hall AK, Burke RM, Anand M, Dinsio KJ | title = Activin and bone morphogenetic proteins are present in perinatal sensory neuron target tissues that induce neuropeptides | journal = Journal of Neurobiology | volume = 52 | issue = 1 | pages = 52–60 | date = July 2002 | pmid = 12115893 | doi = 10.1002/neu.10068 }}
* {{cite journal | vauthors = Groppe J, Greenwald J, Wiater E, Rodriguez-Leon J, Economides AN, Kwiatkowski W, Affolter M, Vale WW, Izpisua Belmonte JC, Choe S | title = Structural basis of BMP signalling inhibition by the cystine knot protein Noggin | journal = Nature | volume = 420 | issue = 6916 | pages = 636–42 | date = Dec 2002 | pmid = 12478285 | doi = 10.1038/nature01245 }}
* {{cite journal | vauthors = Groppe J, Greenwald J, Wiater E, Rodriguez-Leon J, Economides AN, Kwiatkowski W, Affolter M, Vale WW, Izpisua Belmonte JC, Choe S | title = Structural basis of BMP signalling inhibition by the cystine knot protein Noggin | journal = Nature | volume = 420 | issue = 6916 | pages = 636–42 | date = December 2002 | pmid = 12478285 | doi = 10.1038/nature01245 }}
* {{cite journal | vauthors = Brown DJ, Kim TB, Petty EM, Downs CA, Martin DM, Strouse PJ, Moroi SE, Gebarski SS, Lesperance MM | title = Characterization of a stapes ankylosis family with a NOG mutation | journal = Otology & Neurotology | volume = 24 | issue = 2 | pages = 210–5 | date = Mar 2003 | pmid = 12621334 | doi = 10.1097/00129492-200303000-00014 }}
* {{cite journal | vauthors = Brown DJ, Kim TB, Petty EM, Downs CA, Martin DM, Strouse PJ, Moroi SE, Gebarski SS, Lesperance MM | title = Characterization of a stapes ankylosis family with a NOG mutation | journal = Otology & Neurotology | volume = 24 | issue = 2 | pages = 210–5 | date = March 2003 | pmid = 12621334 | doi = 10.1097/00129492-200303000-00014 }}
{{refend}}
{{refend}}


== External links ==
== External links ==
* [http://wikis.fu-berlin.de/x/R4Gq BMPedia - the Bone Morphogenetic Protein Wiki]
* [http://wikis.fu-berlin.de/x/R4Gq BMPedia - the Bone Morphogenetic Protein Wiki]{{dead link|date=February 2018 |bot=InternetArchiveBot |fix-attempted=yes }}
* [http://www.xenbase.org/gene/showgene.do?method=display&geneId=487723 Noggin publications, gene expression data, sequences and interactants from Xenbase]  
* [http://www.xenbase.org/gene/showgene.do?method=display&geneId=487723 Noggin publications, gene expression data, sequences and interactants from Xenbase]  
* {{UCSC genome browser|NOG}}
* {{UCSC genome browser|NOG}}

Latest revision as of 19:01, 19 December 2018

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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.[1] 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 English-language word for "head", was coined in reference to its ability to produce embryos with large heads when exposed at high concentrations.[2]

Function

Noggin is a signaling molecule that plays an important role in promoting somite patterning in the developing embryo.[3] It is released from the notochord and regulates bone morphogenic protein (BMP4) during development.[4] 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.[4]

Noggin function is required for correct nervous system, somite, and skeletal development.[4] Experiments in mice have shown that noggin also plays a role in learning, cognition,[5] bone development,[6] and neural tube fusion.[7] 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).[4] SYNS1 is different from SYM1 by causing hip and vertebral fusions.[4] The embryo may also develop shorter bones, miss any skeletal elements, or lack multiple articulating joints.[4]

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.

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 canal, 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.[8]

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.[9]

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.[10]

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.[9]

All these NOG mutations have altered evolutionarily conserved amino acid residues.

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 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.[11]

References

  1. ↑ "Entrez Gene: NOG noggin".
  2. ↑ Oppenheimer SB (1995). "The Discovery of Noggin". The American Biology Teacher. 57 (5): 264. doi:10.2307/4449989. hdl:10211.2/1126. JSTOR 4449989.
  3. ↑ Hirsinger E, Duprez D, Jouve C, Malapert P, Cooke J, Pourquié O (November 1997). "Noggin acts downstream of Wnt and Sonic Hedgehog to antagonize BMP4 in avian somite patterning". Development. 124 (22): 4605–14. PMID 9409677.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 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. doi:10.1073/pnas.201367598. PMC 58733. PMID 11562478.
  5. ↑ Xu H, Huang W, Wang Y, Sun W, Tang J, Li D, Xu P, Guo L, Yin ZQ, Fan X (January 2013). "The function of BMP4 during neurogenesis in the adult hippocampus in Alzheimer's disease". Ageing Research Reviews. 12 (1): 157–64. doi:10.1016/j.arr.2012.05.002. PMID 22698853.
  6. ↑ Potti TA, Petty EM, Lesperance MM (August 2011). "A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related-symphalangism spectrum disorder (NOG-SSD)". Human Mutation. 32 (8): 877–86. doi:10.1002/humu.21515. PMID 21538686.
  7. ↑ Liu A, Niswander LA (December 2005). "Bone morphogenetic protein signalling and vertebrate nervous system development". Nature Reviews. Neuroscience. 6 (12): 945–54. doi:10.1038/nrn1805. PMID 16340955.
  8. ↑ Bok J, Brunet LJ, Howard O, Burton Q, Wu DK (November 2007). "Role of hindbrain in inner ear morphogenesis: analysis of Noggin knockout mice". Developmental Biology. 311 (1): 69–78. doi:10.1016/j.ydbio.2007.08.013. PMC 2215324. PMID 17900554.
  9. ↑ 9.0 9.1 Krause C, Guzman A, Knaus P (April 2011). "Noggin". The International Journal of Biochemistry & Cell Biology. 43 (4): 478–81. doi:10.1016/j.biocel.2011.01.007. PMID 21256973.
  10. ↑ Masuda S, Namba K, Mutai H, Usui S, Miyanaga Y, Kaneko H, Matsunaga T (May 2014). "A mutation in the heparin-binding site of noggin as a novel mechanism of proximal symphalangism and conductive hearing loss". Biochemical and Biophysical Research Communications. 447 (3): 496–502. doi:10.1016/j.bbrc.2014.04.015. PMID 24735539.
  11. ↑ 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". The Journal of Neuroscience. 15 (9): 6077–84. PMID 7666191.

Further reading

External links

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