Doublecortin
Encyclopedia
Doublecortex; lissencephaly, X-linked (doublecortin), also known as DCX, is a gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

.

Doublecortin (DCX) is a microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...

-associated protein expressed by neuronal precursor cells and immature neurons in embryonic and adult cortical structures. Neuronal precursor cells begin to express DCX while actively dividing, and their neuronal daughter cells continue to express DCX for 2–3 weeks as the cells mature into neurons. Downregulation of DCX begins after 2 weeks, and occurs at the same time that these cells begin to express, NeuN
NeuN
]NeuN is a neuronal nuclear antigen and was first described in 1994 by Mullen et al., who raised a series of monoclonal antibodies to mouse antigens with the original intent of finding mouse species specific immunological markers for use in transplantation experiments...

, a marker for mature neurons.

Due to the nearly exclusive expression of DCX in developing neurons, this protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 has been used increasingly as a marker for neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...

. Indeed, the levels of DCX expression increase in response to exercise, which occurs in parallel with increased BrdU labelling, currently a "gold standard" in measuring neurogenesis.

Doublecortin was found to bind to the microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...

 cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...

. In vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

and in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...

assays show that Doublecortin stabilises microtubules and causes bundling. Doublecortin is a basic
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...

 protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 with an iso-electric point of 10, typical of microtubule-binding proteins
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

. However, its sequence
Sequence (biology)
A sequence in biology is the one-dimensional ordering of monomers, covalently linked within in a biopolymer; it is also referred to as the primary structure of the biological macromolecule.-See also:* Protein sequence* DNA sequence...

 contains no known microtubule-binding domain(s).

The detailed sequence
Sequence
In mathematics, a sequence is an ordered list of objects . Like a set, it contains members , and the number of terms is called the length of the sequence. Unlike a set, order matters, and exactly the same elements can appear multiple times at different positions in the sequence...

 analysis of Doublecortin and Doublecortin-like proteins allowed the identification of an evolutionarily conserved Doublecortin (DC) domain
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...

. This domain is found in the N terminus of proteins and consists of one or two tandemly repeated copies of an around 80 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s region. It has been suggested that the first DC domain of Doublecortin binds tubulin
Tubulin
Tubulin is one of several members of a small family of globular proteins. The most common members of the tubulin family are α-tubulin and β-tubulin, the proteins that make up microtubules. Each has a molecular weight of approximately 55 kiloDaltons. Microtubules are assembled from dimers of α- and...

 and enhances microtubule polymerisation.

Interactions

Doublecortin has been shown to interact
Protein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...

 with PAFAH1B1
PAFAH1B1
Platelet-activating factor acetylhydrolase IB subunit alpha is an enzyme that in humans is encoded by the PAFAH1B1 gene.According to one study, PAFAH1B1 interacts with VLDLR receptor activated by reelin.-Genomics:...

.

Relevance to Human disease

Doublecortin is mutated in humans in the syndrome X-linked Lissencephaly and double cortex, X-linked lissencephaly means that the disease produce a smooth brain because of lack of migration of immature neurons, without the normal folds of the brain surface. In the case of double cortex the disease is characterized by abnormal migration during development that results in two bands of misplaced neurons in the subcortical white matter that generate two cortex, giving the name to the syndrome, clinically patients with X-linked lissencephaly, the majority of times are males with a mutation in the their X chromosome. In the case of double cortex the majority of the patients are females with a mutation in one of the X-chromosome, they presents intractable seizures and mental retardation. The severity of the disease can be implied by a gene dosage effect, meaning that in the case of males, with only one X chromosome, there is no protein, however in the case of females with two X chromosome, the mutation in one X chromosome can somehow be compensated, however not enough functional protein is produced in the double cortex patients. The mutation was discovered by Joseph Gleeson and Gene Hunter Christopher A. Walsh in Boston.

Further reading

External links

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