Neuronal migration protein doublecortin, also known as doublin or lissencephalin-X is a protein that in humans is encoded by the DCX gene.[5]

DCX
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesDCX, DBCN, DC, LISX, SCLH, XLIS, doublecortin
External IDsOMIM: 300121; MGI: 1277171; HomoloGene: 7683; GeneCards: DCX; OMA:DCX - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001110222
NM_001110223
NM_001110224
NM_010025

RefSeq (protein)

NP_001103692
NP_001103693
NP_001103694
NP_034155

Location (UCSC)Chr X: 111.29 – 111.41 MbChr X: 142.64 – 142.72 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

edit
 
Doublecortin expression in the rat dentate gyrus, 21st postnatal day. Oomen et al., 2009.[6]

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.[7]

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,[8] 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.[9] Doublecortin is a basic protein with an iso-electric point of 10 typical of microtubule-binding proteins.


Knock out mouse

edit
 
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.[10]

Structure

edit
Doublecortin
 
solution structure of the N-terminal dcx domain of human doublecortin-like kinase
Identifiers
SymbolDCX
PfamPF03607
InterProIPR003533
SCOP21mfw / SCOPe / SUPFAM
CDDcd01617
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure 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.[11]

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

edit

Doublecortin has been shown to interact with PAFAH1B1.[12]

Clinical significance

edit

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.[13] The mutation was discovered by Joseph Gleeson and Christopher A. Walsh in Boston.[14][15] At least 49 disease-causing mutations in this gene have been discovered.[16]

See also

edit

References

edit
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000077279Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031285Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ EntrezGene 1641
  6. ^ Oomen CA, Girardi CE, Cahyadi R, Verbeek EC, Krugers H, Joëls M, Lucassen PJ (2009). "Opposite effects of early maternal deprivation on neurogenesis in male versus female rats". PLOS ONE. 4 (1): e3675. Bibcode:2009PLoSO...4.3675O. doi:10.1371/journal.pone.0003675. PMC 2629844. PMID 19180242.
  7. ^ Brown JP, Couillard-Després S, Cooper-Kuhn CM, Winkler J, Aigner L, Kuhn HG (December 2003). "Transient expression of doublecortin during adult neurogenesis". J. Comp. Neurol. 467 (1): 1–10. doi:10.1002/cne.10874. PMID 14574675. S2CID 25315374.
  8. ^ Couillard-Despres S, Winner B, Schaubeck S, Aigner R, Vroemen M, Weidner N, Bogdahn U, Winkler J, Kuhn HG, Aigner L (January 2005). "Doublecortin expression levels in adult brain reflect neurogenesis". Eur. J. Neurosci. 21 (1): 1–14. doi:10.1111/j.1460-9568.2004.03813.x. PMID 15654838. S2CID 45893767.
  9. ^ Horesh D, Sapir T, Francis F, Wolf SG, Caspi M, Elbaum M, Chelly J, Reiner O (September 1999). "Doublecortin, a stabilizer of microtubules". Hum. Mol. Genet. 8 (9): 1599–610. doi:10.1093/hmg/8.9.1599. PMID 10441322.
  10. ^ Nosten-Bertrand M, Kappeler C, Dinocourt C, Denis C, Germain J, Phan Dinh Tuy F, Verstraeten S, Alvarez C, Métin C, Chelly J, Giros B, Miles R, Depaulis A, Francis F (2008-06-25). "Epilepsy in Dcx knockout mice associated with discrete lamination defects and enhanced excitability in the hippocampus". PLOS ONE. 3 (6): e2473. Bibcode:2008PLoSO...3.2473N. doi:10.1371/journal.pone.0002473. PMC 2429962. PMID 18575605.
  11. ^ Sapir T, Horesh D, Caspi M, Atlas R, Burgess HA, Wolf SG, Francis F, Chelly J, Elbaum M, Pietrokovski S, Reiner O (March 2000). "Doublecortin mutations cluster in evolutionarily conserved functional domains". Hum. Mol. Genet. 9 (5): 703–12. doi:10.1093/hmg/9.5.703. PMID 10749977.
  12. ^ Caspi M, Atlas R, Kantor A, Sapir T, Reiner O (September 2000). "Interaction between LIS1 and doublecortin, two lissencephaly gene products". Hum. Mol. Genet. 9 (15): 2205–13. doi:10.1093/oxfordjournals.hmg.a018911. PMID 11001923.
  13. ^ Online Mendelian Inheritance in Man (OMIM): Doublecortin - 300121
  14. ^ Gleeson JG, Allen KM, Fox JW, Lamperti ED, Berkovic S, Scheffer I, Cooper EC, Dobyns WB, Minnerath SR, Ross ME, Walsh CA (January 1998). "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. doi:10.1016/S0092-8674(00)80899-5. PMID 9489700.
  15. ^ Lowenstein DH (2011). "Seizures and Epilepsy". In Loscalzo J, Longo DL, Fauci AS, Kasper DL, Hauser SL (eds.). Harrison's Principles of Internal Medicine (18th ed.). McGraw-Hill Professional. pp. 3251–3269. ISBN 978-0-07-174889-6.
  16. ^ Šimčíková D, Heneberg P (December 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC 6901466. PMID 31819097.

Further reading

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