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.[7]
Noggin function is required for correct nervous system, somite, and skeletal development.[9] Experiments in mice have shown that noggin also plays a role in learning, cognition,[10]bone development,[11] and neural tube fusion.[12] 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).[9] SYNS1 is different from SYM1 by causing hip and vertebral fusions.[9] The embryo may also develop shorter bones, miss any skeletal elements, or lack multiple articulating joints.[9]
Increased plasma levels of Noggin have been observed in obese mice and in patients with a body mass index over 27.[13] Additionally, it has been shown that Noggin depletion in adipose tissue leads to obesity.[14]
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.[15]
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-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.[14]
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.[16]
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.[17]
Recently, several heterozygousmissense 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.[16]
Mutations in this gene have been associated with middle ear abnormalities.[18]
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.[19]
^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. PMID22698853. S2CID46528212.
^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. PMID16340955. S2CID1005572.
^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. PMID24735539.
^Lindquist NR, Appelbaum EN, Acharya A, Vrabec JT, Leal SM, Schrauwen I (2019) A start codon variant in NOG underlies symphalangism and ossicular chain malformations affecting both the incus and the stapes. Case Rep Genet 2019:2836263
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. PMID10087923.
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. PMID10080184. S2CID652235.
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. PMID10657699. S2CID35547875.
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. PMID11846737. S2CID29452724.
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. PMID12115893.
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. PMID12478285. S2CID4386654.
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. PMID12621334. S2CID26445733.
