Noggin (protein)

Protein coding gene in the species Homo sapiens

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). 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.

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. 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). Additionally, it has been shown that Noggin depletion in adipose tissue leads to obesity.

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.

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 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. 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.

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.