- Email: [email protected]
Reeler Locus
Ree ler Lo cus 1649 homologous chromosomes during meiosis. It occurs in regions of the genome where homologs differ by the presence or absence of one or more inversions that suppress normal pairing and crossing-over. Loci within the extent of the inversion become completely linked and cannot be resolved by traditional mapping methods. See also: Inversion
etiological role for EBV in the pathogenesis of this tumor.
Further Reading
Diehl V (ed.) (1996) Hodgkin's Disease. London: BallieÁre Tindall.
See also: Epstein±Barr Virus (EBV); Hodgkin's Disease
Reeler Locus Recombinational Repair S A Lacks Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.1084
Some DNA repair processes depend on the pairing of homologous DNA segments and recombinational mechanisms otherwise used for genetic exchange. These processes intervene when there is no local template for repair, as there is for damage in a single strand. Instead, sister chromosomes or homologs provide the template. Double-strand breaks in DNA are repaired by recombinational mechanisms in species ranging from bacteria to humans. These mechanisms may include but do not require recombination of chromosomal markers flanking the damage. See also: Repair Mechanisms
Reed±Sternberg Cells R Marcus Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.1611
Reed±Sternberg (R±S) cells are large binucleate cells, 15±45 mm in diameter with abundant slightly basophilic cytoplasm, and prominent nucleoli. Their presence in the appropriate morphological background of lymphocytes, eosinophils, and plasma cells is diagnostic of Hodgkin's disease. Originally described by Sternberg (1898) and independently by Reed (1902), these cells are of uncertain origin, but recent evidence showing clonal Ig rearrangement in individual R±S cells strongly points to a B-cell origin. Clonal Epstein± Barr virus (EBV) genomes and EBV latency associated proteins found in R±S cells also suggest an
R H Reeves Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.1090
The reeler mouse was identified as a spontaneous recessive mutation in 1951. It is characterized grossly by ataxia, especially locomotion involving the hind limbs, and displays variable viability and fertility on different inbred or outbred genetic backgrounds. Histologically, the brains of these mice are disorganized with respect to neuronal placement, and this disruption is especially evident in the highly structured cerebellum, cerebral cortex, and hippocampus. Analysis of the reeler mutation has contributed substantially to the understanding of how neurons find their correct positions during brain ontogenesis, and has implications for important human neurological disorders, including schizophrenia. Disruption of the reelin gene (Reln) was demonstrated to be responsible for the reeler phenotype in 1995. (Accordingly, the gene name and symbol were changed to represent the normal gene product, of which reeler is a mutant allele). Reln is a very large gene, encoding a 12 kb mRNA from 65 exons spanning about 450 kb of genomic DNA. The 10.3 kb open reading frame encodes a protein of 3461 amino acid residues and a relative molecular mass of 388 kDa. Reelin is a secreted glycoprotein characterized by a signal peptide, F-spondin domain, and eight novel repeated domains, each of which contains an EGFlike motif. The protein is highly conserved, showing 94% amino acid identity between mouse and human. The Reln gene maps to mouse chromosome 5 and to a region of conserved synteny on human chromosome 7. Neurons in the developing brains of homozygous reeler mice display a migratory defect resulting in abnormal lamination of the cerebral cortex and cerebellum. The normal cortex is formed by an `inside-out' pattern of migration. Pioneer neurons such as the Cajal±Retzius cells migrate outward from a central ventricular zone along glial fibers, stopping at an
1650
Regulation of DNA Repair
appropriate level. Subsequent waves of cells migrate past layers of already established cells to form successive layers of the cortex. Neurons in the mutant mice are formed and begin to migrate, but do not penetrate the cortical plate formed by the first wave of migrating cells. Ultimately they do form appropriate synaptic connections with other neurons. In other words, they carry out most processes of neuronal development and function, but appear to lack signals necessary to determine their proper positions within the cortex. Substantial advances in understanding how reelin might affect this process have come through the analysis of additional mouse mutations that are near-perfect phenocopies of reeler. Two spontaneous mutations, scrambler and yotari, are both alleles of the Dab1 gene. Dab1 encodes a cytoplasmic protein involved in signal transduction which is regulated by tyrosine phosphorylation. It is expressed in the migrating neurons that fail to find their appropriate positions in reeler mice. Dab1 expression levels are significantly elevated in the absence of reelin, but levels of phosphorylated protein are decreased. Reelin has no known Dab1-independent functions. In addition to these spontaneously occurring Dab1 mutations, the reeler phenotype is also closely recapitulated in a genetically engineered mouse in which two low-density lipoprotein family receptors, the ApoE and VLDL receptors, are both deleted (ApoER2 -/-, VLDLR -/-). Together with the Dab1 -/- phenocopies of reeler, these observations suggest a pathway for signaling to determine neuronal placement involving these separate elements. Several lines of experimental evidence suggest that ApoER2 and VLDLR act as receptors for the secreted reelin glycoprotein, although this mechanism is not yet proven in vivo. An additional co-receptor may be required for reelin signaling, as well. Transmembrane proteins of the cadherin-related neuronal (CNR) receptor family are implicated both by an appropriate pattern and timing of expression, and from in vitro binding studies. Like all LDL family receptors, ApoER2 and VLDLR transmembrane proteins both contain a cytoplasmic FXNPXY signal, and the Dab1 protein has a binding domain that interacts with this signal. Further, the CNR receptors transduce signals via tyrosine kinases of the src family. If a CNR serves as the coreceptor for reelin with ApoER2 or VLDLR, Dab1 binding to the FXNPXY signal in the activated receptor would thus bring it into proximity of a tyrosine kinase associated with the CNR. The absence of phosphorylated Dab1 in reeler mice could then be explained, since Dab1 would not be expected to associate with the receptor unless it first binds reelin.
Even if the reelin-LDLR/CNR-Dab1 model proves to accurately reflect the cellular signaling pathway for neuronal positioning during development, the Reln gene may prove to have further roles operating via different pathways in adults. Analysis of the brains of schizophrenics demonstrated a reduction of reelin mRNA and protein to levels 50% of normal, with no effect on the level of Dab1 expression. Substantial characterization remains to be done to fully understand this gene and its multiple roles in the complex organization and function of the brain in normal and pathological situations.
Further Reading
Cooper, JA and Howell, BW (1999) Lipoprotein receptors: signaling functions in the brain? Cell 97: 671±674. Rice, DS and Curran, T (1999) Mutant mice with scrambled brains: understanding the signaling pathways that control cell positioning in the CNS. Genes and Development 13: 2758 ±2773.
See also: Neuronal Guidance; Neuronal Specification; Schizophrenia
Regulation of DNA Repair M Ambrose and L D Samson Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.1091
DNA is inherently unstable and susceptible to modification by a broad range of environmental agents, including ultraviolet (UV) light and ionizing radiation. In addition, it is widely appreciated that the stability of cellular DNA can be compromized by purely endogenous processes, which include spontaneous enzymatic attack, spontaneous base loss, and reaction of oxidizing and alkylating chemical agents formed during normal cellular metabolic processes. Given the importance of maintaining the structural integrity of the DNA molecule, it is not surprising to find that organisms ranging from bacteria to Homo sapiens have a number of DNA repair pathways that are capable of recognizing and repairing many different types of DNA lesions. In general, organisms have at their disposal constitutively produced DNA repair proteins that primarily serve to prevent and resolve low levels of DNA damage in an essentially `error-free' fashion. In some cases, DNA damage can be repaired by catalyzing the direct chemical reversal of the damage (e.g., by constitutively expressed photoreactivating and alkyltransferase proteins). Other more complex constitutively
etiological role for EBV in the pathogenesis of this tumor.
Further Reading
Diehl V (ed.) (1996) Hodgkin's Disease. London: BallieÁre Tindall.
See also: Epstein±Barr Virus (EBV); Hodgkin's Disease
Reeler Locus Recombinational Repair S A Lacks Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.1084
Some DNA repair processes depend on the pairing of homologous DNA segments and recombinational mechanisms otherwise used for genetic exchange. These processes intervene when there is no local template for repair, as there is for damage in a single strand. Instead, sister chromosomes or homologs provide the template. Double-strand breaks in DNA are repaired by recombinational mechanisms in species ranging from bacteria to humans. These mechanisms may include but do not require recombination of chromosomal markers flanking the damage. See also: Repair Mechanisms
Reed±Sternberg Cells R Marcus Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.1611
Reed±Sternberg (R±S) cells are large binucleate cells, 15±45 mm in diameter with abundant slightly basophilic cytoplasm, and prominent nucleoli. Their presence in the appropriate morphological background of lymphocytes, eosinophils, and plasma cells is diagnostic of Hodgkin's disease. Originally described by Sternberg (1898) and independently by Reed (1902), these cells are of uncertain origin, but recent evidence showing clonal Ig rearrangement in individual R±S cells strongly points to a B-cell origin. Clonal Epstein± Barr virus (EBV) genomes and EBV latency associated proteins found in R±S cells also suggest an
R H Reeves Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.1090
The reeler mouse was identified as a spontaneous recessive mutation in 1951. It is characterized grossly by ataxia, especially locomotion involving the hind limbs, and displays variable viability and fertility on different inbred or outbred genetic backgrounds. Histologically, the brains of these mice are disorganized with respect to neuronal placement, and this disruption is especially evident in the highly structured cerebellum, cerebral cortex, and hippocampus. Analysis of the reeler mutation has contributed substantially to the understanding of how neurons find their correct positions during brain ontogenesis, and has implications for important human neurological disorders, including schizophrenia. Disruption of the reelin gene (Reln) was demonstrated to be responsible for the reeler phenotype in 1995. (Accordingly, the gene name and symbol were changed to represent the normal gene product, of which reeler is a mutant allele). Reln is a very large gene, encoding a 12 kb mRNA from 65 exons spanning about 450 kb of genomic DNA. The 10.3 kb open reading frame encodes a protein of 3461 amino acid residues and a relative molecular mass of 388 kDa. Reelin is a secreted glycoprotein characterized by a signal peptide, F-spondin domain, and eight novel repeated domains, each of which contains an EGFlike motif. The protein is highly conserved, showing 94% amino acid identity between mouse and human. The Reln gene maps to mouse chromosome 5 and to a region of conserved synteny on human chromosome 7. Neurons in the developing brains of homozygous reeler mice display a migratory defect resulting in abnormal lamination of the cerebral cortex and cerebellum. The normal cortex is formed by an `inside-out' pattern of migration. Pioneer neurons such as the Cajal±Retzius cells migrate outward from a central ventricular zone along glial fibers, stopping at an
1650
Regulation of DNA Repair
appropriate level. Subsequent waves of cells migrate past layers of already established cells to form successive layers of the cortex. Neurons in the mutant mice are formed and begin to migrate, but do not penetrate the cortical plate formed by the first wave of migrating cells. Ultimately they do form appropriate synaptic connections with other neurons. In other words, they carry out most processes of neuronal development and function, but appear to lack signals necessary to determine their proper positions within the cortex. Substantial advances in understanding how reelin might affect this process have come through the analysis of additional mouse mutations that are near-perfect phenocopies of reeler. Two spontaneous mutations, scrambler and yotari, are both alleles of the Dab1 gene. Dab1 encodes a cytoplasmic protein involved in signal transduction which is regulated by tyrosine phosphorylation. It is expressed in the migrating neurons that fail to find their appropriate positions in reeler mice. Dab1 expression levels are significantly elevated in the absence of reelin, but levels of phosphorylated protein are decreased. Reelin has no known Dab1-independent functions. In addition to these spontaneously occurring Dab1 mutations, the reeler phenotype is also closely recapitulated in a genetically engineered mouse in which two low-density lipoprotein family receptors, the ApoE and VLDL receptors, are both deleted (ApoER2 -/-, VLDLR -/-). Together with the Dab1 -/- phenocopies of reeler, these observations suggest a pathway for signaling to determine neuronal placement involving these separate elements. Several lines of experimental evidence suggest that ApoER2 and VLDLR act as receptors for the secreted reelin glycoprotein, although this mechanism is not yet proven in vivo. An additional co-receptor may be required for reelin signaling, as well. Transmembrane proteins of the cadherin-related neuronal (CNR) receptor family are implicated both by an appropriate pattern and timing of expression, and from in vitro binding studies. Like all LDL family receptors, ApoER2 and VLDLR transmembrane proteins both contain a cytoplasmic FXNPXY signal, and the Dab1 protein has a binding domain that interacts with this signal. Further, the CNR receptors transduce signals via tyrosine kinases of the src family. If a CNR serves as the coreceptor for reelin with ApoER2 or VLDLR, Dab1 binding to the FXNPXY signal in the activated receptor would thus bring it into proximity of a tyrosine kinase associated with the CNR. The absence of phosphorylated Dab1 in reeler mice could then be explained, since Dab1 would not be expected to associate with the receptor unless it first binds reelin.
Even if the reelin-LDLR/CNR-Dab1 model proves to accurately reflect the cellular signaling pathway for neuronal positioning during development, the Reln gene may prove to have further roles operating via different pathways in adults. Analysis of the brains of schizophrenics demonstrated a reduction of reelin mRNA and protein to levels 50% of normal, with no effect on the level of Dab1 expression. Substantial characterization remains to be done to fully understand this gene and its multiple roles in the complex organization and function of the brain in normal and pathological situations.
Further Reading
Cooper, JA and Howell, BW (1999) Lipoprotein receptors: signaling functions in the brain? Cell 97: 671±674. Rice, DS and Curran, T (1999) Mutant mice with scrambled brains: understanding the signaling pathways that control cell positioning in the CNS. Genes and Development 13: 2758 ±2773.
See also: Neuronal Guidance; Neuronal Specification; Schizophrenia
Regulation of DNA Repair M Ambrose and L D Samson Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.1091
DNA is inherently unstable and susceptible to modification by a broad range of environmental agents, including ultraviolet (UV) light and ionizing radiation. In addition, it is widely appreciated that the stability of cellular DNA can be compromized by purely endogenous processes, which include spontaneous enzymatic attack, spontaneous base loss, and reaction of oxidizing and alkylating chemical agents formed during normal cellular metabolic processes. Given the importance of maintaining the structural integrity of the DNA molecule, it is not surprising to find that organisms ranging from bacteria to Homo sapiens have a number of DNA repair pathways that are capable of recognizing and repairing many different types of DNA lesions. In general, organisms have at their disposal constitutively produced DNA repair proteins that primarily serve to prevent and resolve low levels of DNA damage in an essentially `error-free' fashion. In some cases, DNA damage can be repaired by catalyzing the direct chemical reversal of the damage (e.g., by constitutively expressed photoreactivating and alkyltransferase proteins). Other more complex constitutively