Noggin (protein)

Noggin, also known as NOG, is a is_associated_with::protein that is involved in the development of many body tissues, including nerve tissue, muscles, and bones. In humans is encoded by the NOG is_associated_with::gene. The amino acid sequence of human noggin is highly homologous to that of is_associated_with::rat, is_associated_with::mouse, and is_associated_with::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.

Function
Noggin is a signaling molecule that plays an important role in promoting is_associated_with::somite patterning in the developing embryo. It is released from the is_associated_with::notochord and regulates bone morphogenic protein 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 is_associated_with::missense mutations in the noggin gene can cause deformities such as joint fusions and syndromes such as multiple is_associated_with::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.

Noggin is essential for proper bone and limb development, and it carries out many processes that are essential for proper neural development in the embryo.

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 mouse knockout model was studied tracking the extent to which the absence of noggin on the embryological development. The focus of the model was the ear formation and its cause in conductive hearing loss. The inner ear underwent multiple deformations affecting the is_associated_with::cochlear duct, is_associated_with::semilunar canal, and otic capsule portions. Noggin was also shown to be indirectly involved in the malformations through its interaction with the notochord and neural axis. The kinking of the is_associated_with::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 role of BMP as the major source of deformation rather than noggin having a direct effect on inner ear development.

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 is_associated_with::ectoderm germ layer. Noggin activity in the is_associated_with::mesoderm gives way to the formation of cartilage, bone and muscle growth, and in the is_associated_with::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 is_associated_with::heterozygous missense human NOG mutations in unrelated families with is_associated_with::proximal symphalangism (SYM1) and is_associated_with::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 is_associated_with::chromosome 17 (17q22) as NOG. These mutations indicate functional is_associated_with::haploinsufficiency where the is_associated_with::homozygous forms are embryonically lethal.

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

Discovery
Noggin was originally isolated from the aquatic-frog genus ''is_associated_with::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 is_associated_with::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.