Biology:Doublecortin

Short description: Protein-coding gene in humans

Generic protein structure example

Neuronal migration protein doublecortin, also known as doublin or lissencephalin-X is a protein that in humans is encoded by the DCX gene.

Function

Doublecortin expression in the rat dentate gyrus, 21st postnatal day. Oomen et al., 2009.

Doublecortin (DCX) is a microtubule-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, a neuronal marker.

Due to the nearly exclusive expression of DCX in developing neurons, this protein has been used increasingly as a marker for neurogenesis. Indeed, levels of DCX expression increase in response to exercise, and that increase occurs in parallel with increased BrdU labeling, which is currently a "gold standard" in measuring neurogenesis.

Doublecortin was found to bind to the microtubule cytoskeleton. In vivo and in vitro assays show that Doublecortin stabilizes microtubules and causes bundling. Doublecortin is a basic protein with an iso-electric point of 10 typical of microtubule-binding proteins.

Knock out mouse

Double layer hippocampus seen in Doublecortin knock out mice (right panels) compared to the normal hippocampus in wild type mice (left panels). Figure extracted from the work of the laboratory of Fiona Francis

In mice where the Doublecortin gene has been knocked out, cortical layers are still correctly formed. However, the hippocampi of these mice show disorganisation in the CA3 region. The normally single layer of pyramidal cells in mutants is seen as a double layer. These mice also have different behavior than their wild type littermates and are epileptic.

Structure

Doublecortin
solution structure of the N-terminal dcx domain of human doublecortin-like kinase
Identifiers
Symbol	DCX
Pfam	PF03607
InterPro	IPR003533
SCOP2	1mfw / SCOPe / SUPFAM
CDD	cd01617
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

The detailed sequence analysis of Doublecortin and Doublecortin-like proteins allowed the identification of a tandem repeat of evolutionarily conserved Doublecortin (DC) domains. These domains are found in the N terminus of proteins and consists of tandemly repeated copies of an around 80 amino acids region. It has been suggested that the first DC domain of Doublecortin binds tubulin and enhances microtubule polymerisation.

Doublecortin has been shown to influence the structure of microtubules. Microtubule nucleated in vitro in the presence of Doublecortin have almost exclusively 13 protofilaments, whereas microtubule nucleated without Doublecortin are present in a range of different sizes.

Interactions

Doublecortin has been shown to interact with PAFAH1B1.

Clinical significance

Doublecortin is mutated in X-linked lissencephaly and the double cortex syndrome, and the clinical manifestations are sex-linked. In males, X-linked lissencephaly produces a smooth brain due to lack of migration of immature neurons, which normally promote folding of the brain surface. Double cortex syndrome is characterized by abnormal migration of neural tissue during development which results in two bands of misplaced neurons within the subcortical white, generating two cortices, giving the name to the syndrome; this finding generally occurs in females. The mutation was discovered by Joseph Gleeson and Christopher A. Walsh in Boston. At least 49 disease-causing mutations in this gene have been discovered.

See also

• Lissencephaly

Further reading

• "Dominant X linked subcortical laminar heterotopia and lissencephaly syndrome (XSCLH/LIS): evidence for the occurrence of mutation in males and mapping of a potential locus in Xq22.". J. Med. Genet. 34 (3): 177–83. 1997. doi:10.1136/jmg.34.3.177. PMID 9132485. 
• "A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome.". Cell 92 (1): 51–61. 1998. doi:10.1016/S0092-8674(00)80898-3. PMID 9489699. 
• "Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein.". Cell 92 (1): 63–72. 1998. doi:10.1016/S0092-8674(00)80899-5. PMID 9489700. 
• "doublecortin is the major gene causing X-linked subcortical laminar heterotopia (SCLH).". Hum. Mol. Genet. 7 (7): 1063–70. 1999. doi:10.1093/hmg/7.7.1063. PMID 9618162. 
• "Human doublecortin (DCX) and the homologous gene in mouse encode a putative Ca2+-dependent signaling protein which is mutated in human X-linked neuronal migration defects.". Hum. Mol. Genet. 7 (8): 1327–32. 1998. doi:10.1093/hmg/7.8.1327. PMID 9668176. 
• "LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation.". Hum. Mol. Genet. 7 (13): 2029–37. 1999. doi:10.1093/hmg/7.13.2029. PMID 9817918. 
• "Characterization of mutations in the gene doublecortin in patients with double cortex syndrome.". Ann. Neurol. 45 (2): 146–53. 1999. doi:10.1002/1531-8249(199902)45:2<146::AID-ANA3>3.0.CO;2-N. PMID 9989615. 
• "A novel mutation of the doublecortin gene in Japanese patients with X-linked lissencephaly and subcortical band heterotopia.". Hum. Genet. 104 (4): 341–4. 1999. doi:10.1007/s004390050963. PMID 10369164. 
• "Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons.". Neuron 23 (2): 257–71. 1999. doi:10.1016/S0896-6273(00)80778-3. PMID 10399933. 
• "Subcortical band heterotopia in rare affected males can be caused by missense mutations in DCX (XLIS) or LIS1.". Hum. Mol. Genet. 8 (9): 1757–60. 2000. doi:10.1093/hmg/8.9.1757. PMID 10441340. 
• "Genetic alteration of the DCX gene in Japanese patients with subcortical laminar heterotopia or isolated lissencephaly sequence.". J. Hum. Genet. 45 (3): 167–70. 2000. doi:10.1007/s100380050204. PMID 10807542. 
• "Interaction between LIS1 and doublecortin, two lissencephaly gene products.". Hum. Mol. Genet. 9 (15): 2205–13. 2001. doi:10.1093/oxfordjournals.hmg.a018911. PMID 11001923. 
• "Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopia.". Eur. J. Hum. Genet. 9 (1): 5–12. 2001. doi:10.1038/sj.ejhg.5200548. PMID 11175293. 
• "Incomplete penetrance with normal MRI in a woman with germline mutation of the DCX gene.". Neurology 57 (2): 327–30. 2001. doi:10.1212/wnl.57.2.327. PMID 11468322. 
• "Doublecortin interacts with mu subunits of clathrin adaptor complexes in the developing nervous system.". Mol. Cell. Neurosci. 18 (3): 307–19. 2001. doi:10.1006/mcne.2001.1022. PMID 11591131. 
• "Mutation of the doublecortin gene in male patients with double cortex syndrome: somatic mosaicism detected by hair root analysis.". Ann. Neurol. 50 (4): 547–51. 2001. doi:10.1002/ana.1231. PMID 11601509. 
• "So-called 'cryptogenic' partial seizures resulting from a subtle cortical dysgenesis due to a doublecortin gene mutation.". Seizure: The Journal of the British Epilepsy Association 11 (4): 273–7. 2002. doi:10.1053/seiz.2001.0607. PMID 12027577. 
• "A new activity of doublecortin in recognition of the phospho-FIGQY tyrosine in the cytoplasmic domain of neurofascin.". J. Neurosci. 22 (18): 7948–58. 2002. doi:10.1523/JNEUROSCI.22-18-07948.2002. PMID 12223548. 
• "Subcortical band heterotopia (SBH) in males: clinical, imaging and genetic findings in comparison with females.". Brain 125 (Pt 11): 2507–22. 2002. doi:10.1093/brain/awf248. PMID 12390976. 
• "Selective expression of doublecortin and LIS1 in developing human cortex suggests unique modes of neuronal movement.". Cereb. Cortex 12 (12): 1225–36. 2003. doi:10.1093/cercor/12.12.1225. PMID 12427674. 

External links

• GeneReviews/NCBI/NIH/UW entry on DCX-Related Disorders
• OMIM entries on DCX-Related Disorders
• doublecortin+protein at the US National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: O43602 (Neuronal migration protein doublecortin) at the PDBe-KB.

This article incorporates text from the public domain Pfam and InterPro: IPR003533