Noggin, also known as NOG, is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that is involved in the development of many
body tissues, including
nerve tissue
Nervous tissue, also called neural tissue, is the main tissue component of the nervous system. The nervous system regulates and controls body functions and activity. It consists of two parts: the central nervous system (CNS) comprising the brain ...
,
muscles
Muscle is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to muscle contra ...
, and
bone
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...
s. In humans, noggin is encoded by the ''NOG''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
The
amino acid sequence
Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthe ...
of human noggin is highly homologous to that of
rat
Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include '' Neotoma'' (pack rats), '' Bandicota'' (bandicoo ...
,
mouse
A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus'' ...
, and ''
Xenopus
''Xenopus'' () (Gk., ξενος, ''xenos'' = strange, πους, ''pous'' = foot, commonly known as the clawed frog) is a genus of highly aquatic frogs native to sub-Saharan Africa. Twenty species are currently described with ...
'' (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.
Function
Noggin is a
signaling molecule
In biology, cell signaling (cell signalling in British English) is the Biological process, process by which a Cell (biology), cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all Cell (biol ...
that plays an important role in promoting
somite
The somites (outdated term: primitive segments) are a set of bilaterally paired blocks of paraxial mesoderm that form in the embryogenesis, embryonic stage of somitogenesis, along the head-to-tail axis in segmentation (biology), segmented animals. ...
patterning in the
developing embryo.
It is released from the
notochord
The notochord is an elastic, rod-like structure found in chordates. In vertebrates the notochord is an embryonic structure that disintegrates, as the vertebrae develop, to become the nucleus pulposus in the intervertebral discs of the verteb ...
and regulates
bone morphogenic protein 4 (BMP4) during development.
The absence of BMP4 will cause the patterning of the
neural tube
In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural folds become elevated, ...
and somites from the
neural plate
In embryology, the neural plate is a key Development of the human body, developmental structure that serves as the basis for the nervous system. Cranial to the primitive node of the embryonic primitive streak, Ectoderm, ectodermal tissue thickens ...
in the developing embryo. It also causes formation of the head and other dorsal structures.
Noggin function is required for correct
nervous system
In biology, the nervous system is the complex system, highly complex part of an animal that coordinates its behavior, actions and sense, sensory information by transmitting action potential, signals to and from different parts of its body. Th ...
, somite, and skeletal development.
Experiments in mice have shown that noggin also plays a role in
learning
Learning is the process of acquiring new understanding, knowledge, behaviors, skills, value (personal and cultural), values, Attitude (psychology), attitudes, and preferences. The ability to learn is possessed by humans, non-human animals, and ...
,
cognition
Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...
,
bone development, and neural tube fusion. Heterozygous
missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn alt ...
s in the noggin gene can cause deformities such as joint fusions and syndromes such as multiple
synostosis
Synostosis (; plural: synostoses) is fusion of two or more bones. It can be normal in puberty (e.g. fusion of the epiphyseal plate to become the epiphyseal line), or abnormal. When synostosis is abnormal it is a type of dysostosis. Examples of ...
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.
Increased plasma levels of Noggin have been observed in obese mice and in patients with a
body mass index
Body mass index (BMI) is a value derived from the mass (Mass versus weight, weight) and height of a person. The BMI is defined as the human body weight, body mass divided by the square (algebra), square of the human height, body height, and is ...
over 27. Additionally, it has been shown that Noggin depletion in
adipose tissue
Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, Blood vessel, vascular endothel ...
leads to
obesity
Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...
.
Mechanism of action
The secreted polypeptide noggin, encoded by the NOG gene, binds and inactivates members of the transforming growth factor-beta (
TGF-beta
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...
) 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
Pleiotropy () is a condition in which a single gene or genetic variant influences multiple phenotypic traits. A gene that has such multiple effects is referred to as a ''pleiotropic gene''. Mutations in pleiotropic genes can impact several trait ...
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
Conductive hearing loss (CHL) is a type of hearing impairment that occurs when sound waves are unable to efficiently travel through the outer ear, tympanic membrane (eardrum), or middle ear structures such as the ossicles. This blockage or dysfun ...
. The inner ear underwent multiple deformations affecting the
cochlear duct Cochlear, the adjective form of cochlea, may refer to:
* Cochlear implant, a sensory aid for the deaf
* Cochlear nuclei, the ventral cochlear nucleus and the dorsal (or lateral) cochlear nucleus
* Vestibular-cochlear or Vestibulocochlear nerve, ...
,
semicircular canal
The semicircular canals are three semicircular interconnected tubes located in the innermost part of each ear, the inner ear. The three canals are the lateral, anterior and posterior semicircular canals. They are the part of the bony labyrinth, ...
s, and
otic capsule portions. Noggin's involvement in the malformations was also shown to be indirect, through its interaction with the
notochord
The notochord is an elastic, rod-like structure found in chordates. In vertebrates the notochord is an embryonic structure that disintegrates, as the vertebrae develop, to become the nucleus pulposus in the intervertebral discs of the verteb ...
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
The hindbrain, rhombencephalon (shaped like a rhombus) is a developmental categorization of portions of the central nervous system in vertebrates. It includes the medulla, pons, and cerebellum. Together they support vital bodily processes.
Met ...
. Major signaling molecules from the
rhombomere
In the vertebrate embryo, a rhombomere is a transiently divided segment of the developing neural tube, within the hindbrain region (a neuromere) in the area that will eventually become the rhombencephalon. The rhombomeres appear as a series of sl ...
structures in the hindbrain could not properly induce
inner ear
The inner ear (internal ear, auris interna) is the innermost part of the vertebrate ear. In vertebrates, the inner ear is mainly responsible for sound detection and balance. In mammals, it consists of the bony labyrinth, a hollow cavity in the ...
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
adipocyte
Adipocytes, also known as lipocytes and fat cells, are the cell (biology), cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through ...
s 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
White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind is brown adipose tissue. White adipose tissue is composed of monolocular Adipocyte, adipocytes.
In humans, the healthy body fat percent ...
, along with
brown fat dysfunction (impaired
thermogenesis
Thermogenesis is the process of heat production in organisms. It occurs in all warm-blooded animals, and also in a few species of thermogenic plants such as the Eastern skunk cabbage, the Voodoo lily ('' Sauromatum venosum''), and the giant w ...
and
β-oxidation) that results in dramatic increases of body weight and percent body fat that causes alterations in the
lipid profile
A lipid profile or lipid panel is a Test panel, panel of blood tests used to find abnormalities in blood lipid ( such as cholesterol and triglycerides) concentrations. The results of this test can identify certain Inborn error of lipid metabolis ...
and in the liver; the effects vary with gender.
Clinical significance
Noggin proteins play a role in
germ layer
A germ layer is a primary layer of cell (biology), cells that forms during embryonic development. The three germ layers in vertebrates are particularly pronounced; however, all eumetazoans (animals that are sister taxa to the sponges) produce tw ...
-specific derivation of specialized cells. The formation of neural tissues, the notochord,
hair follicle
The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction betwee ...
s, and eye structures arise from the
ectoderm
The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from the o ...
germ layer. Noggin activity in the
mesoderm
The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical ...
gives way to the formation of
cartilage
Cartilage is a resilient and smooth type of connective tissue. Semi-transparent and non-porous, it is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints ...
, bone and muscle growth, and in the
endoderm
Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gastr ...
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
The palate () is the roof of the mouth in humans and other mammals. It separates the oral cavity from the nasal cavity.
A similar structure is found in crocodilians, but in most other tetrapods, the oral and nasal cavities are not truly sep ...
,
mandible
In jawed vertebrates, the mandible (from the Latin ''mandibula'', 'for chewing'), lower jaw, or jawbone is a bone that makes up the lowerand typically more mobilecomponent of the mouth (the upper jaw being known as the maxilla).
The jawbone i ...
and
skull
The skull, or cranium, is typically a bony enclosure around the brain of a vertebrate. In some fish, and amphibians, the skull is of cartilage. The skull is at the head end of the vertebrate.
In the human, the skull comprises two prominent ...
through its interaction with
neural crest cells
The neural crest is a ridge-like structure that is formed transiently between the epidermal ectoderm and neural plate during vertebrate development. Neural crest cells originate from this structure through the epithelial-mesenchymal transition, an ...
. 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
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mos ...
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
Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 84 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total DN ...
(17q22) as NOG. These mutations indicate functional
haploinsufficiency
Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type ...
where the
homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mos ...
forms are embryonically lethal.
All these NOG mutations have altered
evolutionarily conserved amino acid residues
Protein structure is the three-dimensional arrangement of atoms in an amino acid-chain molecule. Proteins are polymers specifically polypeptides formed from sequences of amino acids, which are the monomers of the polymer. A single amino acid m ...
.
Mutations in this gene have been associated with
middle ear
The middle ear is the portion of the ear medial to the eardrum, and distal to the oval window of the cochlea (of the inner ear).
The mammalian middle ear contains three ossicles (malleus, incus, and stapes), which transfer the vibrations ...
abnormalities.
[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]
Discovery
Noggin was originally isolated from the aquatic-frog genus ''
Xenopus
''Xenopus'' () (Gk., ξενος, ''xenos'' = strange, πους, ''pous'' = foot, commonly known as the clawed frog) is a genus of highly aquatic frogs native to sub-Saharan Africa. Twenty species are currently described with ...
. ''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
Ultraviolet radiation, also known as simply UV, is electromagnetic radiation of wavelengths of 10–400 nanometers, shorter than that of visible light, but longer than X-rays. UV radiation is present in sunlight and constitutes about 10% of ...
treatment. Noggin was discovered in the laboratory of
Richard M. Harland and William C. Smith at the
University of California, Berkeley
The University of California, Berkeley (UC Berkeley, Berkeley, Cal, or California), is a Public university, public Land-grant university, land-grant research university in Berkeley, California, United States. Founded in 1868 and named after t ...
because of this ability to induce secondary axis formation in frog embryos.
References
Further reading
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External links
BMPedia - the Bone Morphogenetic Protein WikiNoggin publications, gene expression data, sequences and interactants from Xenbase
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{{TGFβ receptor superfamily modulators
Developmental genes and proteins