DAB1
Protein-coding gene in the species Homo sapiens

DAB1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesDAB1, reelin adaptor protein
External IDsOMIM: 603448; MGI: 108554; HomoloGene: 32084; GeneCards: DAB1; OMA:DAB1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1600

13131

Ensembl

ENSG00000173406

ENSMUSG00000028519

UniProt

O75553

P97318

RefSeq (mRNA)

NM_021080

RefSeq (protein)
Location (UCSC)n/aChr 4: 103.62 – 104.74 Mb
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

The Disabled-1 (Dab1) gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathwaythat controls cell positioning in the developing brain and during adult neurogenesis. It docks to the intracellular part of the Reelin very low density lipoprotein receptor (VLDLR) and apoE receptor type 2 (ApoER2) and becomes tyrosine-phosphorylated following binding of Reelin to cortical neurons. In mice, mutations of Dab1 and Reelin generate identical phenotypes. In humans, Reelin mutations are associated with brain malformations and mental retardation. In mice, Dab1 mutation results in the scrambler mouse phenotype.

With a genomic length of 1.1 Mbp for a coding region of 5.5 kb, DAB1 provides a rare example of genomic complexity, which will impede the identification of human mutations.

Gene function

Cortical neurons form in specialized proliferative regions deep in the brain and migrate past previously formed neurons to reach their proper layer. The laminar organization of multiple neuronal types in the cerebral cortex is required for normal cognitive function. The mouse 'reeler' mutation causes abnormal patterns of cortical neuronal migration as well as additional defects in cerebellar development and neuronal positioning in other brain regions. Reelin (RELN; 600514), the reeler gene product, is an extracellular protein secreted by pioneer neurons. The mouse 'scrambler' and 'yotari' recessive mutations exhibit a phenotype identical to that of reeler. Ware et al. (1997) determined that the scrambler phenotype arises from mutations in Dab1, a mouse gene related to the Drosophila gene 'disabled' (dab).[4] Disabled-1 (Dab1) is an adaptor protein that is essential for the intracellular transduction of Reelin signaling, which regulates the migration and differentiation of postmitotic neurons during brain development in vertebrates. Dab1 function depends on its tyrosine phosphorylation by Src family kinases, especially Fyn.[5] Dab encodes a phosphoprotein that binds nonreceptor tyrosine kinases and that has been implicated in neuronal development in flies. Sheldon et al. (1997) found that the yotari phenotype also results from a mutation in the Dab1 gene.[6] Using in situ hybridization to embryonic day-13.5 mouse brain tissue, they demonstrated that Dab1 is expressed in neuronal populations exposed to reelin. The authors concluded that reelin and Dab1 function as signaling molecules that regulate cell positioning in the developing brain. Howell et al. (1997) showed that targeted disruption of the Dab1 gene disturbed neuronal layering in the cerebral cortex, hippocampus, and cerebellum, causing a reeler-like phenotype.[7]

Layering of neurons in the cerebral cortex and cerebellum requires RELN and DAB1. By targeted disruption experiments in mice, Trommsdorff et al. (1999) showed that 2 cell surface receptors, very low density lipoprotein receptor (VLDLR; 192977) and apolipoprotein E receptor-2 (ApoER2; 602600), are also required.[8] Both receptors bound Dab1 on their cytoplasmic tails and were expressed in cortical and cerebellar layers adjacent to layers expressing Reln. Dab1 expression was upregulated in knockout mice lacking both the Vldlr and Apoer2 genes. Inversion of cortical layers, absence of cerebellar foliation, and the migration of Purkinje cells in these animals precisely mimicked the phenotype of mice lacking Reln or Dab1. These findings established novel signaling functions for the LDL receptor gene family and suggested that VLDLR and APOER2 participate in transmitting the extracellular RELN signal to intracellular signaling processes initiated by DAB1.

In the reeler mouse, the telencephalic neurons (which are misplaced following migration) express approximately 10-fold more DAB1 than their wildtype counterpart. Such an increase in the expression of a protein that virtually functions as a receptor is expected to occur when the specific signal for the receptor is missing.[9]

Pathology

Mutations of the DAB1 gene can cause spinocerebellar ataxia type 37. The fact that mutations of the DAB1 gene are also linked to Alzheimer's disease (AD) has been explained by the hypothetic role of reelin signaling in AD.[10]

Gene variants and associated phenotypes in humans

In a study by Dr. Scott Williamson of Cornell University, a newer version of the DAB1 gene had been shown to be universal among those of Chinese ancestry, but not found among other global populations.[11]

References

  1. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028519 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ Ware M, Fox J, González J, Davis N, Lambert de Rouvroit C, Russo C, Chua S, Goffinet A, Walsh C (1997). "Aberrant splicing of a mouse disabled homolog, mdab1, in the scrambler mouse". Neuron. 19 (2): 239–49. doi:10.1016/S0896-6273(00)80936-8. PMID 9292716. S2CID 1273677.
  5. ^ Long H, Bock HH, Lei T, Chai X, Yuan J, Herz J, Frotscher M, Yang Z (February 2011). "Identification of alternatively spliced Dab1 and Fyn isoforms in pig". BMC Neurosci. 12: 17. doi:10.1186/1471-2202-12-17. PMC 3044655. PMID 21294906.
  6. ^ Sheldon M, Rice DS, D'Arcangelo G, et al. (October 1997). "Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice". Nature. 389 (6652): 730–3. Bibcode:1997Natur.389..730S. doi:10.1038/39601. PMID 9338784. S2CID 4414738.
  7. ^ Howell B, Hawkes R, Soriano P, Cooper J (1997). "Neuronal position in the developing brain is regulated by mouse disabled-1". Nature. 389 (6652): 733–7. Bibcode:1997Natur.389..733H. doi:10.1038/39607. PMID 9338785. S2CID 4327765.
  8. ^ Trommsdorff M, Gotthardt M, Hiesberger T, Shelton J, Stockinger W, Nimpf J, Hammer R, Richardson J, Herz J (1999). "Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2". Cell. 97 (6): 689–701. doi:10.1016/S0092-8674(00)80782-5. PMID 10380922. S2CID 13492626.
  9. ^ Online Mendelian Inheritance in Man (OMIM): REELIN; RELN - 600514
  10. ^ Kovács KA (December 2021). "Relevance of a Novel Circuit-Level Model of Episodic Memories to Alzheimer's Disease". International Journal of Molecular Sciences. 23 (1): 462. doi:10.3390/ijms23010462. PMC 8745479. PMID 35008886.
  11. ^ Williamson SH, Hubisz MJ, Clark AG, Payseur BA, Bustamante CD, Nielsen R (2007). "Localizing Recent Adaptive Evolution in the Human Genome". PLOS Genetics. 3 (6): e90. doi:10.1371/journal.pgen.0030090. PMC 1885279. PMID 17542651.

Further reading

  • Kam R, Chen J, Blümcke I, et al. (2004). "The reelin pathway components disabled-1 and p35 in gangliogliomas--a mutation and expression analysis". Neuropathol. Appl. Neurobiol. 30 (3): 225–32. doi:10.1046/j.0305-1846.2004.00526.x. PMID 15175076. S2CID 24883591.
  • Yasui N, Nogi T, Kitao T, et al. (2007). "Structure of a receptor-binding fragment of reelin and mutational analysis reveal a recognition mechanism similar to endocytic receptors". Proc. Natl. Acad. Sci. U.S.A. 104 (24): 9988–93. Bibcode:2007PNAS..104.9988Y. doi:10.1073/pnas.0700438104. PMC 1891246. PMID 17548821.
  • Huang Y, Shah V, Liu T, Keshvara L (2005). "Signaling through Disabled 1 requires phosphoinositide binding". Biochem. Biophys. Res. Commun. 331 (4): 1460–8. doi:10.1016/j.bbrc.2005.04.064. PMID 15883038.
  • Uhl GR, Liu QR, Drgon T, et al. (2008). "Molecular genetics of successful smoking cessation: convergent genome-wide association study results". Arch. Gen. Psychiatry. 65 (6): 683–93. doi:10.1001/archpsyc.65.6.683. PMC 2430596. PMID 18519826.
  • Feng L, Allen NS, Simo S, Cooper JA (2007). "Cullin 5 regulates Dab1 protein levels and neuron positioning during cortical development". Genes Dev. 21 (21): 2717–30. doi:10.1101/gad.1604207. PMC 2045127. PMID 17974915.
  • Calderwood DA, Fujioka Y, de Pereda JM, et al. (2003). "Integrin beta cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling". Proc. Natl. Acad. Sci. U.S.A. 100 (5): 2272–7. Bibcode:2003PNAS..100.2272C. doi:10.1073/pnas.262791999. PMC 151330. PMID 12606711.
  • McAvoy S, Zhu Y, Perez DS, et al. (2008). "Disabled-1 is a large common fragile site gene, inactivated in multiple cancers". Genes Chromosomes Cancer. 47 (2): 165–74. doi:10.1002/gcc.20519. PMID 18008369. S2CID 24674687.
  • Deguchi K, Inoue K, Avila WE, et al. (2003). "Reelin and disabled-1 expression in developing and mature human cortical neurons". J. Neuropathol. Exp. Neurol. 62 (6): 676–84. doi:10.1093/jnen/62.6.676. PMID 12834112.
  • Hoe HS, Minami SS, Makarova A, et al. (2008). "Fyn modulation of Dab1 effects on amyloid precursor protein and ApoE receptor 2 processing". J. Biol. Chem. 283 (10): 6288–99. doi:10.1074/jbc.M704140200. PMID 18089558.
  • Hoe HS, Tran TS, Matsuoka Y, et al. (2006). "DAB1 and Reelin effects on amyloid precursor protein and ApoE receptor 2 trafficking and processing". J. Biol. Chem. 281 (46): 35176–85. doi:10.1074/jbc.M602162200. PMID 16951405.
  • Ballif BA, Arnaud L, Arthur WT, et al. (2004). "Activation of a Dab1/CrkL/C3G/Rap1 pathway in Reelin-stimulated neurons". Curr. Biol. 14 (7): 606–10. Bibcode:2004CBio...14..606B. doi:10.1016/j.cub.2004.03.038. PMID 15062102. S2CID 52887334.
  • Beffert U, Durudas A, Weeber EJ, et al. (2006). "Functional dissection of Reelin signaling by site-directed disruption of Disabled-1 adaptor binding to apolipoprotein E receptor 2: distinct roles in development and synaptic plasticity". J. Neurosci. 26 (7): 2041–52. doi:10.1523/JNEUROSCI.4566-05.2006. PMC 6674917. PMID 16481437.
  • Yang XV, Banerjee Y, Fernández JA, et al. (2009). "Activated protein C ligation of ApoER2 (LRP8) causes Dab1-dependent signaling in U937 cells". Proc. Natl. Acad. Sci. U.S.A. 106 (1): 274–9. Bibcode:2009PNAS..106..274Y. doi:10.1073/pnas.0807594106. PMC 2629184. PMID 19116273.
  • Morimura T, Hattori M, Ogawa M, Mikoshiba K (2005). "Disabled1 regulates the intracellular trafficking of reelin receptors". J. Biol. Chem. 280 (17): 16901–8. doi:10.1074/jbc.M409048200. PMID 15718228.
  • Lee EJ, Kim HJ, Lim EJ, et al. (2004). "AII amacrine cells in the mammalian retina show disabled-1 immunoreactivity". J. Comp. Neurol. 470 (4): 372–81. doi:10.1002/cne.20010. PMID 14961563. S2CID 12353565.
  • Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
  • Assadi AH, Zhang G, Beffert U, et al. (2003). "Interaction of reelin signaling and Lis1 in brain development". Nat. Genet. 35 (3): 270–6. doi:10.1038/ng1257. PMID 14578885. S2CID 26963397.
  • Honda T, Nakajima K (2006). "Mouse Disabled1 (DAB1) is a nucleocytoplasmic shuttling protein". J. Biol. Chem. 281 (50): 38951–65. doi:10.1074/jbc.M609061200. PMID 17062576.
  • Bar I, Lambert de Rouvroit C, Goffinet AM (2000). "The evolution of cortical development. An hypothesis based on the role of the Reelin signaling pathway". Trends Neurosci. 23 (12): 633–8. doi:10.1016/S0166-2236(00)01675-1. PMID 11137154. S2CID 13568642.
  • Park TJ, Hamanaka H, Ohshima T, et al. (2003). "Inhibition of ubiquitin ligase Siah-1A by disabled-1". Biochem. Biophys. Res. Commun. 302 (4): 671–8. doi:10.1016/S0006-291X(03)00247-X. PMID 12646221.
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