DAB1 5139079 219047216 2008-06-13T09:42:33Z Nagelfar 36259 /* Gene variants & associated phenotypes in humans */ {{protein |Name=disabled homolog 1 (Drosophila) |caption= |image= |width= |HGNCid=2661 |Symbol=DAB1 |AltSymbols= |EntrezGene=1600 |OMIM=603448 |RefSeq=NM_021080 |UniProt=O75553 |PDB= |ECnumber= |Chromosome=1 |Arm=p |Band=32 |LocusSupplementaryData=-p31 }} 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 cell]]s. 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 (biochemistry)|receptor]] ([[VLDL receptor|VLDLR]]) and apoE receptor type 2 ([[ApoER2]]) and becomes tyrosine-phosphorylated following binding of Reelin to cortical neurons. In mice, [[mutation]]s of Dab1 and Reelin generate identical [[phenotype]]s. 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 neuron]]s form in specialized [[proliferative region]]s 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 neuron]]s. The mouse 'scrambler' and '[[yotari]]' [[recessive mutation]]s 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).<ref name="ware">{{cite journal |author=Ware M, Fox J, González J, Davis N, Lambert de Rouvroit C, Russo C, Chua S, Goffinet A, Walsh C |title=Aberrant splicing of a mouse disabled homolog, mdab1, in the scrambler mouse |journal=Neuron |volume=19 |issue=2 |pages=239–49 |year=1997 |pmid=9292716}}</ref> Dab encodes a [[phosphoprotein]] that binds nonreceptor [[tyrosine kinase]]s 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.<ref name="yotari">Sheldon M, Rice DS, D'Arcangelo G, Yoneshima H, Nakajima K, Mikoshiba K, Howell BW, Cooper JA, Goldowitz D, Curran T. (1997) Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice. Nature. 389(6652):730-3. PMID 9338784</ref> 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 molecule]]s 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.<ref name="howell">{{cite journal |author=Howell B, Hawkes R, Soriano P, Cooper J |title=Neuronal position in the developing brain is regulated by mouse disabled-1 |journal=Nature |volume=389 |issue=6652 |pages=733–7 |year=1997 |pmid=9338785 |doi=10.1038/39607}}</ref> 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.<ref name="trommsdorff">{{cite journal |author=Trommsdorff M, Gotthardt M, Hiesberger T, Shelton J, Stockinger W, Nimpf J, Hammer R, Richardson J, Herz J |title=Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2 |journal=Cell |volume=97 |issue=6 |pages=689–701 |year=1999 |pmid=10380922 |doi=10.1016/S0092-8674(00)80782-5}}</ref> Both receptors bound Dab1 on their cytoplasmic tails and were expressed in cortical and cerebellar layers adjacent to layers expressing Reln. Dab1 expression was [[Upregulation|upregulated]] in [[Gene knockout|knockout mice]] lacking both the Vldlr and Apoer2 genes. Inversion of cortical layers, absence of cerebellar foliation, and the migration of [[Purkinje cell]]s 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 neuron]]s (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.<ref>{{cite web |url=http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600514 |title=OMIM - REELIN; RELN |accessdate=2007-09-05}}</ref> == Gene variants & 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 [[Han Chinese|Chinese]] ancestry, but not found among other global populations.<!-- --><ref name="pmid17542651">{{cite journal |author=Williamson SH, Hubisz MJ, Clark AG, Payseur BA, Bustamante CD, Nielsen R |title=Localizing Recent Adaptive Evolution in the Human Genome |journal= |volume=3 |issue=6 |pages=e90 |year=2007 |pmid=17542651 |doi=10.1371/journal.pgen.0030090}}</ref><ref name="NYT1"> [http://www.nytimes.com/2007/06/26/science/26human.html?pagewanted=2&_r=1&ex=1340596800 Humans Have Spread Globally, and Evolved Locally] - The New York Times, 26 June 2007</ref><!-- --> Being related to organizing the cells of the areas in the brain associated with higher cognitive function, it is speculated that the DAB1 mutation in the Chinese may be a parallel genetic evolutionary route to possibly accomplish an equivalent adaptation to other brain gene adaptations found in other world populations (such as the [[ASPM (Gene)|ASPM]] gene variant) but not in the Chinese.<ref name="NYT1"/> ==References== <references/> ==External links== * [http://www.biocarta.com/pathfiles/h_reelinPathway.asp Reelin Signaling Pathway] - DAB1 plays a major role in the Reelin pathway; malfunctions at this pathway are linked to [[schizophrenia]], [[autism]], [[lissencephaly]] and other [[brain diseases]]. * {{UMichOPM|protein|pdbid|1nu2}} * {{MeshName|DAB1+protein,+human}} [[Category:Molecular neuroscience]] [[Category:Genes]] [[Category:Peripheral membrane proteins]] [[Category:Phosphoproteins]] [[Category:Genes associated with genetic disorders]] [[Category:Central nervous system]] [[ru:DAB1]]