Noggin (protein)

Last updated
NOG
Protein NOG PDB 1m4u.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NOG , Nog, SYM1, SYNS1, SYNS1A, noggin
External IDs OMIM: 602991 MGI: 104327 HomoloGene: 3979 GeneCards: NOG
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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 [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] The amino acid sequence of human noggin is highly homologous to that of rat, mouse, and Xenopus (an aquatic frog genus).

Contents

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

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]

Function

Noggin is a signaling molecule that plays an important role in promoting somite patterning in the developing embryo. [8] It is released from the notochord and regulates bone morphogenic protein 4 (BMP4) during development. [9] 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. [9]

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 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. [16]

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

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]

Related Research Articles

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<span class="mw-page-title-main">Somite</span> Each of several blocks of mesoderm that flank the neural tube on either side in embryogenesis

The somites are a set of bilaterally paired blocks of paraxial mesoderm that form in the embryonic stage of somitogenesis, along the head-to-tail axis in segmented animals. In vertebrates, somites subdivide into the dermatomes, myotomes, sclerotomes and syndetomes that give rise to the vertebrae of the vertebral column, rib cage, part of the occipital bone, skeletal muscle, cartilage, tendons, and skin.

<span class="mw-page-title-main">Somitogenesis</span>

Somitogenesis is the process by which somites form. Somites are bilaterally paired blocks of paraxial mesoderm that form along the anterior-posterior axis of the developing embryo in segmented animals. In vertebrates, somites give rise to skeletal muscle, cartilage, tendons, endothelium, and dermis.

<span class="mw-page-title-main">Neural plate</span>

The neural plate is a key developmental structure that serves as the basis for the nervous system. Cranial to the primitive node of the embryonic primitive streak, ectodermal tissue thickens and flattens to become the neural plate. The region anterior to the primitive node can be generally referred to as the neural plate. Cells take on a columnar appearance in the process as they continue to lengthen and narrow. The ends of the neural plate, known as the neural folds, push the ends of the plate up and together, folding into the neural tube, a structure critical to brain and spinal cord development. This process as a whole is termed primary neurulation.

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<span class="mw-page-title-main">Neural crest</span> Pluripotent embyronic cell group giving rise to diverse cell lineages

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<span class="mw-page-title-main">Paraxial mesoderm</span>

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<span class="mw-page-title-main">Chordin-like 1</span> Protein-coding gene in humans

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<span class="mw-page-title-main">HES7 gene</span> Protein-coding gene in humans

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References

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Further reading