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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]]
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|scrambler]]'' mouse phenotype.
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|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.
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 ==
== Gene function ==

Revision as of 17:16, 1 May 2010

Template:PBB

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.

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).[1] 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.[2] 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.[3]

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.[4] 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.[5]

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 Chinese ancestry, but not found among other global populations.[6][7] Being related to organizing the cells of the areas in the brain associated with 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 variant) but not in the Chinese.[7]

References

  1. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Sheldon M, Rice DS, D'Arcangelo G; et al. (1997). "Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice". Nature. 389 (6652): 730–3. doi:10.1038/39601. PMID 9338784. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ 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. doi:10.1038/39607. PMID 9338785.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Online Mendelian Inheritance in Man (OMIM): REELIN; RELN - 600514
  6. ^ 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. PMID 17542651.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  7. ^ a b Humans Have Spread Globally, and Evolved Locally - The New York Times, 26 June 2007

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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • 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. doi:10.1073/pnas.0700438104. PMID 17548821. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • 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. PMID 18519826. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • 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. PMID 17974915.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • 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. doi:10.1073/pnas.262791999. PMID 12606711. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • 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. PMID 12834112. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  • 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  • 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. doi:10.1016/j.cub.2004.03.038. PMID 15062102. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • 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. PMID 16481437. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • 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. doi:10.1073/pnas.0807594106. PMID 19116273. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • 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.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  • 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • 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. PMID 11137154.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • 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. PMID 12646221. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
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