Wikipedia

DAB1

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 pathway that 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.

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

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

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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

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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

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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

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  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

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