Many DNA transactions, such as replication, repair and recombination involve DNA synthesis and co... more Many DNA transactions, such as replication, repair and recombination involve DNA synthesis and consequently require the action of DNA synthesizing enzymes called DNA polymerases (Pol). Eukaryotic cells contain at least six different Pols, named alpha, beta, gamma, delta, epsilon, and zeta. Among them Pol delta occupies important roles in DNA replication, nucleotide excision repair, base excision repair and VDJ recombination. Pol a has been extremely conserved in evolution from yeast to man. The function of Pol delta must be considered in the context of two other factors, called proliferating cell nuclear antigen and replication factor C, two protein complexes that build together the moving platform for Pol delta. This moving platform provides an important framework for dynamic properties of an accurate Pol delta such as its recruitment when its function is needed, the facilitation of Pol delta binding to the primer terminus, the increase in Pol delta processivity, the prevention of ...
The human brain is capable of generating new functional neurons throughout life, a phenomenon kno... more The human brain is capable of generating new functional neurons throughout life, a phenomenon known as adult neurogenesis. The generation of new neurons is sustained throughout adulthood due to the proliferation and differentiation of adult neural stem cells. This process in humans is uniquely located in the subgranular zone of the dentate gyrus in the hippocampus. Adult hippocampal neurogenesis (AHN) is thought to play a major role in hippocampus-dependent functions, such as spatial awareness, long-term memory, emotionality, and mood. The overall aim of current treatments for cancer (such as radiotherapy and chemotherapy) is to prevent aberrant cell division of cell populations associated with malignancy. However, the treatments in question are absolutist in nature and hence inhibit all cell division. An unintended consequence of this cessation of cell division is the impairment of adult neural stem cell proliferation and AHN. Patients undergoing treatment for cancerous malignancies often display specific forms of memory deficits, as well as depressive symptoms. This review aims to discuss the effects of cancer treatments on AHN and propose a link between the inhibition of the neurogenetic process in the hippocampus and the advent of the cognitive and mood-based deficits observed in patients and animal models undergoing cancer therapies. Possible evidence for coadjuvant interventions aiming to protect neural cells, and subsequently the mood and cognitive functions they regulate, from the ablative effects of cancer treatment are discussed as potential clinical tools to improve mental health among cancer patients.
The entire cDNA encoding the large subunit of mouse DNA polymerase δ (mPo1δ; EC 2.7.7.7) has been... more The entire cDNA encoding the large subunit of mouse DNA polymerase δ (mPo1δ; EC 2.7.7.7) has been cloned and expressed in various bacterial expression systems. A soluble protein could only be obtained when mPo1δ was produced as a glutathione S-transferase (GST) fusion protein and the incubation temperature of the expression strain was reduced to 30°C. After purification over a glutathione-Sepharose
During development axons encounter a variety of choice points where they have to make appropriate... more During development axons encounter a variety of choice points where they have to make appropriate pathfinding decisions. The optic chiasm is a major decision point for retinal ganglion cell (RGC) axons en route to their target in order to ensure the correct wiring of the visual system. MicroRNAs (miRNAs) belong to the class of small non-coding RNA molecules and have been identified as important regulators of a variety of processes during embryonic development. However, their involvement in axon guidance decisions is less clear. We report here that the early loss of Dicer, an essential protein for the maturation of miRNAs, in all cells of the forming retina and optic chiasm leads to severe phenotypes of RGC axon pathfinding at the midline. Using a conditional deletion approach in mice, we find in homozygous Dicer mutants a marked increase of ipsilateral projections, RGC axons extending outside the optic chiasm, the formation of a secondary optic tract and a substantial number of RGC ...
Advances in experimental medicine and biology, 2007
Page 1. CHAPTER 3 Eph Receptors and Ephrin Ligands in Axon Guidance Michael Reber,* Robert Hindge... more Page 1. CHAPTER 3 Eph Receptors and Ephrin Ligands in Axon Guidance Michael Reber,* Robert Hindges and GregLemke Introduction The Eph tyrosine kinase receptors (a receptor family named for the expression ofEph ...
We report that EphB receptors direct unique axonal behaviors required for mapping the dorsal-vent... more We report that EphB receptors direct unique axonal behaviors required for mapping the dorsal-ventral (D-V) retinal axis along the lateral-medial (L-M) axis of the superior colliculus (SC). EphBs are expressed in a D-V gradient, ephrin-B1 in a L-M gradient in SC, and ephrin-B3 at its midline. EphBs and ephrin-Bs are expressed in countergradients in retina and SC. Developmental analyses reveal that retinal axons lack D-V ordering along the L-M axis, but directionally extend branches along it to establish ordered arbors. Directed branch extension is disrupted in EphB2; EphB3-deficient mice resulting in lateral ectopic arbors. Mice with kinase-inactive EphB2 have similar D-V mapping defects indicating that forward signaling dominates over reverse signaling. Our data suggest that branches of EphB expressing axons are attracted medially by ephrin-B1, and provide molecular mechanisms for D-V mapping in visual centers.
The vertebrate retina is highly ordered along both its dorsoventral (DV) and nasotemporal (NT) ax... more The vertebrate retina is highly ordered along both its dorsoventral (DV) and nasotemporal (NT) axes, and this order is topographically maintained in its axonal connections to the superior colliculus of the midbrain. Although the graded axon guidance cues that mediate the topographic mapping of retinocollicular connections are increasingly well understood, the transcriptional regulators that set the DV and NT gradients of these cues are not. We now provide genetic evidence that Vax2, a homeodomain protein expressed in the ventral retina, is one such regulator. We demonstrate that in Vax2 mutant mice, retinocollicular projections from the ventral temporal retina are dorsalized relative to wild type. Remarkably, however, this dorsalization becomes systematically less severe in progressively more nasal regions of the ventral retina. Vax2 mutants also exhibit flattened DV and NT gradients of the EphA5, EphB2, EphB3, ephrin-B1 and ephrin-B2 axon guidance cues. Together, these data identif...
Many DNA transactions, such as replication, repair and recombination involve DNA synthesis and co... more Many DNA transactions, such as replication, repair and recombination involve DNA synthesis and consequently require the action of DNA synthesizing enzymes called DNA polymerases (Pol). Eukaryotic cells contain at least six different Pols, named alpha, beta, gamma, delta, epsilon, and zeta. Among them Pol delta occupies important roles in DNA replication, nucleotide excision repair, base excision repair and VDJ recombination. Pol a has been extremely conserved in evolution from yeast to man. The function of Pol delta must be considered in the context of two other factors, called proliferating cell nuclear antigen and replication factor C, two protein complexes that build together the moving platform for Pol delta. This moving platform provides an important framework for dynamic properties of an accurate Pol delta such as its recruitment when its function is needed, the facilitation of Pol delta binding to the primer terminus, the increase in Pol delta processivity, the prevention of ...
The human brain is capable of generating new functional neurons throughout life, a phenomenon kno... more The human brain is capable of generating new functional neurons throughout life, a phenomenon known as adult neurogenesis. The generation of new neurons is sustained throughout adulthood due to the proliferation and differentiation of adult neural stem cells. This process in humans is uniquely located in the subgranular zone of the dentate gyrus in the hippocampus. Adult hippocampal neurogenesis (AHN) is thought to play a major role in hippocampus-dependent functions, such as spatial awareness, long-term memory, emotionality, and mood. The overall aim of current treatments for cancer (such as radiotherapy and chemotherapy) is to prevent aberrant cell division of cell populations associated with malignancy. However, the treatments in question are absolutist in nature and hence inhibit all cell division. An unintended consequence of this cessation of cell division is the impairment of adult neural stem cell proliferation and AHN. Patients undergoing treatment for cancerous malignancies often display specific forms of memory deficits, as well as depressive symptoms. This review aims to discuss the effects of cancer treatments on AHN and propose a link between the inhibition of the neurogenetic process in the hippocampus and the advent of the cognitive and mood-based deficits observed in patients and animal models undergoing cancer therapies. Possible evidence for coadjuvant interventions aiming to protect neural cells, and subsequently the mood and cognitive functions they regulate, from the ablative effects of cancer treatment are discussed as potential clinical tools to improve mental health among cancer patients.
The entire cDNA encoding the large subunit of mouse DNA polymerase δ (mPo1δ; EC 2.7.7.7) has been... more The entire cDNA encoding the large subunit of mouse DNA polymerase δ (mPo1δ; EC 2.7.7.7) has been cloned and expressed in various bacterial expression systems. A soluble protein could only be obtained when mPo1δ was produced as a glutathione S-transferase (GST) fusion protein and the incubation temperature of the expression strain was reduced to 30°C. After purification over a glutathione-Sepharose
During development axons encounter a variety of choice points where they have to make appropriate... more During development axons encounter a variety of choice points where they have to make appropriate pathfinding decisions. The optic chiasm is a major decision point for retinal ganglion cell (RGC) axons en route to their target in order to ensure the correct wiring of the visual system. MicroRNAs (miRNAs) belong to the class of small non-coding RNA molecules and have been identified as important regulators of a variety of processes during embryonic development. However, their involvement in axon guidance decisions is less clear. We report here that the early loss of Dicer, an essential protein for the maturation of miRNAs, in all cells of the forming retina and optic chiasm leads to severe phenotypes of RGC axon pathfinding at the midline. Using a conditional deletion approach in mice, we find in homozygous Dicer mutants a marked increase of ipsilateral projections, RGC axons extending outside the optic chiasm, the formation of a secondary optic tract and a substantial number of RGC ...
Advances in experimental medicine and biology, 2007
Page 1. CHAPTER 3 Eph Receptors and Ephrin Ligands in Axon Guidance Michael Reber,* Robert Hindge... more Page 1. CHAPTER 3 Eph Receptors and Ephrin Ligands in Axon Guidance Michael Reber,* Robert Hindges and GregLemke Introduction The Eph tyrosine kinase receptors (a receptor family named for the expression ofEph ...
We report that EphB receptors direct unique axonal behaviors required for mapping the dorsal-vent... more We report that EphB receptors direct unique axonal behaviors required for mapping the dorsal-ventral (D-V) retinal axis along the lateral-medial (L-M) axis of the superior colliculus (SC). EphBs are expressed in a D-V gradient, ephrin-B1 in a L-M gradient in SC, and ephrin-B3 at its midline. EphBs and ephrin-Bs are expressed in countergradients in retina and SC. Developmental analyses reveal that retinal axons lack D-V ordering along the L-M axis, but directionally extend branches along it to establish ordered arbors. Directed branch extension is disrupted in EphB2; EphB3-deficient mice resulting in lateral ectopic arbors. Mice with kinase-inactive EphB2 have similar D-V mapping defects indicating that forward signaling dominates over reverse signaling. Our data suggest that branches of EphB expressing axons are attracted medially by ephrin-B1, and provide molecular mechanisms for D-V mapping in visual centers.
The vertebrate retina is highly ordered along both its dorsoventral (DV) and nasotemporal (NT) ax... more The vertebrate retina is highly ordered along both its dorsoventral (DV) and nasotemporal (NT) axes, and this order is topographically maintained in its axonal connections to the superior colliculus of the midbrain. Although the graded axon guidance cues that mediate the topographic mapping of retinocollicular connections are increasingly well understood, the transcriptional regulators that set the DV and NT gradients of these cues are not. We now provide genetic evidence that Vax2, a homeodomain protein expressed in the ventral retina, is one such regulator. We demonstrate that in Vax2 mutant mice, retinocollicular projections from the ventral temporal retina are dorsalized relative to wild type. Remarkably, however, this dorsalization becomes systematically less severe in progressively more nasal regions of the ventral retina. Vax2 mutants also exhibit flattened DV and NT gradients of the EphA5, EphB2, EphB3, ephrin-B1 and ephrin-B2 axon guidance cues. Together, these data identif...
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Papers by Robert Hindges