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Role of the pRb family proteins in axon guidance and axon tract formation
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Abstracts / Int. J. Devl Neuroscience 47 (2015) 1–131
damage due to HI manifests as decreased hippocampal and cortical volume, and/or enlargement of the ventricles. Additionally, HI is associated with later cognitive and behavioral deficits such as language and memory impairments, as well as attentional deficits (e.g. ADHD), and these are often more severe in males. The current study utilized an animal model of HI injury, where male and female rats received induced brain damage on postnatal day 7. We sought to assess sex differences on a rapid auditory processing task, spatial and non-spatial memory tasks, and a 5choice serial reaction time task of visual attention in HI males and females as compared to shams. Based on prior evidence in our lab showing more robust behavioral deficits in males, it was hypothesized that on all behavioral tasks, male HI rodents would yield significant behavioral deficits while female HI rodents would yield subtle or no behavioral deficits. Results revealed significant deficits in RAP and spatial and nonspatial learning in HI males, thereby replicating previous findings. HI males were also impaired in visual attention, providing a novel finding. HI females displayed a subtle impairment on RAP and no significant deficits on spatial and non-spatial learning, but did display significant deficits in visual attention similar to HI males. Anatomical results also revealed that both HI males and females displayed significant and comparable right hemisphere damage in the cortex, hippocampus and ventricles. The similar pattern of anatomical injury in both sexes, combined with differences in behavior, suggest that there may be different mechanisms of reorganization following injury, leading to a female “advantage” in outcomes for some but not all behavioral domains.
mid-pregnancy (MNR). Animals were necropsied near-term for fetal measures, and fetal brains were immersion-fixed for later assessment of necrotic cell injury using standard H&E criteria. Significance was assumed for p < 0.05. Results: Nine control (31 fetuses) and twelve MNR (42 fetuses) sows were necropsied with MNR fetal weights decreased 28%. Select AGA-control (n = 18) and FGR-MNR (n = 18) fetuses underwent full necropsy; fetal weights decreased 37%, brain weights decreased 12% and brain to liver weight ratios increased 48%. Overall, low levels of necrotic appearing cells were observed in studied brain regions, averaging 0.45/HPF and 0.59/HPF (40×) for control and MNR animals, respectively. Many values were not significantly different from zero, with no differences between control and MNR groups. Discussion: MNR in guinea pigs results in FGR with small livers relative to brain weight. This likely reflects a degree of blood flow redistribution, characteristic of asymmetrical FGR seen with “placental insufficiency”. These fetuses have reduced brain weights, but with substantial “brain sparing” relative to decreased body weights, and with no increased necrotic cell injury indicating that the threshold for membrane failure with energy depletion has likely not been reached. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.251 ISDN2014 0305 Role of the pRb family proteins in axon guidance and axon tract formation
http://dx.doi.org/10.1016/j.ijdevneu.2015.04.250
D. Svoboda ∗ , D.S. Park, R.S. Slack
ISDN2014 0304
Department of Neuroscience/Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Rd, Ottawa ON K1H8M5, Canada
Maternal nutrient restriction (MNR) in pregnant guinea pigs and the impact on fetal growth and brain development Andrew Ghaly 1,∗ , Alex Xu 1 , Karen Nygard 4 , Brad Matushewski 3 , Robert Hammond 2 , Bryan S. Richardson 1,3 , A. Elias 1 1 Departments of Physiology and Pharmacology, Children’s Health Research Institute, Western University, London, Ontario, Canada 2 Departments of Pathology, Children’s Health Research Institute, Western University, London, Ontario, Canada 3 Departments of Obstetrics, Children’s Health Research Institute, Western University, London, Ontario, Canada 4 Departments of Gynecology and Science, Children’s Health Research Institute, Western University, London, Ontario, Canada
Introduction: Maternal undernourishment in guinea pigs results in placental structural abnormalities. This reduces nutrient transport, decreasing birth weight by ∼30%. However, whether brain weights are similarly reduced, or preserved by “brain sparing” mechanisms, and whether energy levels are depleted causing increased structural cell damage, due to membrane failure remains unknown. Our purpose was to determine the extent to which MNR in guinea pigs as a causative factor for fetal growth restriction (FGR) impacts brain growth, the degree of “brain sparing”, and membrane failure via quantifying brain weight, brain to liver weight ratios and cellular necrosis. Methods: Guinea pig sows were fed ad libitum (Control) or 70% of the control diet pre-pregnancy switching to 90% at
Neuron development proceeds through a series of stages beginning with division of neural precursor cells and birth of the neuron, and culminating with neuronal maturation. To maintain organization of this complex chain of events, later stage events, like axon tract formation, must be coordinated with the culmination of earlier events such as cell cycle exit and terminal differentiation. In support of this, there is increasing evidence that proteins which regulate cell cycle progression also influence later events in neuron maturation such as differentiation and migration. We show here that pRb and p107, which are well known to regulate passage into S phase of the cell cycle and therefore control cell cycle exit, also regulate commissural axon tract formation in the developing brain. Following loss of pRb and p107 in the telencephalon, the axons of the corpus callosum and hippocampal commissure fail to cross the midline. The corticoseptal boundary is shifted ventro-caudally in double knockout brains and there are in the midline glial structures, which are well known to have axon guidance functions. In addition, commissural axons travelling through the intermediate zone towards the midline were highly disorganized. To understand why commissural axons fail to cross the midline, we examined expression of a panel of classic axon guidance molecules using in situ hybridization observed deregulation of a number of key molecules known to contribute to commissural axon crossing. This data indicates that the pRb family proteins are crucial for commissural plate development and regulate neuron maturation beyond control of proliferation. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.252
Abstracts / Int. J. Devl Neuroscience 47 (2015) 1–131
damage due to HI manifests as decreased hippocampal and cortical volume, and/or enlargement of the ventricles. Additionally, HI is associated with later cognitive and behavioral deficits such as language and memory impairments, as well as attentional deficits (e.g. ADHD), and these are often more severe in males. The current study utilized an animal model of HI injury, where male and female rats received induced brain damage on postnatal day 7. We sought to assess sex differences on a rapid auditory processing task, spatial and non-spatial memory tasks, and a 5choice serial reaction time task of visual attention in HI males and females as compared to shams. Based on prior evidence in our lab showing more robust behavioral deficits in males, it was hypothesized that on all behavioral tasks, male HI rodents would yield significant behavioral deficits while female HI rodents would yield subtle or no behavioral deficits. Results revealed significant deficits in RAP and spatial and nonspatial learning in HI males, thereby replicating previous findings. HI males were also impaired in visual attention, providing a novel finding. HI females displayed a subtle impairment on RAP and no significant deficits on spatial and non-spatial learning, but did display significant deficits in visual attention similar to HI males. Anatomical results also revealed that both HI males and females displayed significant and comparable right hemisphere damage in the cortex, hippocampus and ventricles. The similar pattern of anatomical injury in both sexes, combined with differences in behavior, suggest that there may be different mechanisms of reorganization following injury, leading to a female “advantage” in outcomes for some but not all behavioral domains.
mid-pregnancy (MNR). Animals were necropsied near-term for fetal measures, and fetal brains were immersion-fixed for later assessment of necrotic cell injury using standard H&E criteria. Significance was assumed for p < 0.05. Results: Nine control (31 fetuses) and twelve MNR (42 fetuses) sows were necropsied with MNR fetal weights decreased 28%. Select AGA-control (n = 18) and FGR-MNR (n = 18) fetuses underwent full necropsy; fetal weights decreased 37%, brain weights decreased 12% and brain to liver weight ratios increased 48%. Overall, low levels of necrotic appearing cells were observed in studied brain regions, averaging 0.45/HPF and 0.59/HPF (40×) for control and MNR animals, respectively. Many values were not significantly different from zero, with no differences between control and MNR groups. Discussion: MNR in guinea pigs results in FGR with small livers relative to brain weight. This likely reflects a degree of blood flow redistribution, characteristic of asymmetrical FGR seen with “placental insufficiency”. These fetuses have reduced brain weights, but with substantial “brain sparing” relative to decreased body weights, and with no increased necrotic cell injury indicating that the threshold for membrane failure with energy depletion has likely not been reached. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.251 ISDN2014 0305 Role of the pRb family proteins in axon guidance and axon tract formation
http://dx.doi.org/10.1016/j.ijdevneu.2015.04.250
D. Svoboda ∗ , D.S. Park, R.S. Slack
ISDN2014 0304
Department of Neuroscience/Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Rd, Ottawa ON K1H8M5, Canada
Maternal nutrient restriction (MNR) in pregnant guinea pigs and the impact on fetal growth and brain development Andrew Ghaly 1,∗ , Alex Xu 1 , Karen Nygard 4 , Brad Matushewski 3 , Robert Hammond 2 , Bryan S. Richardson 1,3 , A. Elias 1 1 Departments of Physiology and Pharmacology, Children’s Health Research Institute, Western University, London, Ontario, Canada 2 Departments of Pathology, Children’s Health Research Institute, Western University, London, Ontario, Canada 3 Departments of Obstetrics, Children’s Health Research Institute, Western University, London, Ontario, Canada 4 Departments of Gynecology and Science, Children’s Health Research Institute, Western University, London, Ontario, Canada
Introduction: Maternal undernourishment in guinea pigs results in placental structural abnormalities. This reduces nutrient transport, decreasing birth weight by ∼30%. However, whether brain weights are similarly reduced, or preserved by “brain sparing” mechanisms, and whether energy levels are depleted causing increased structural cell damage, due to membrane failure remains unknown. Our purpose was to determine the extent to which MNR in guinea pigs as a causative factor for fetal growth restriction (FGR) impacts brain growth, the degree of “brain sparing”, and membrane failure via quantifying brain weight, brain to liver weight ratios and cellular necrosis. Methods: Guinea pig sows were fed ad libitum (Control) or 70% of the control diet pre-pregnancy switching to 90% at
Neuron development proceeds through a series of stages beginning with division of neural precursor cells and birth of the neuron, and culminating with neuronal maturation. To maintain organization of this complex chain of events, later stage events, like axon tract formation, must be coordinated with the culmination of earlier events such as cell cycle exit and terminal differentiation. In support of this, there is increasing evidence that proteins which regulate cell cycle progression also influence later events in neuron maturation such as differentiation and migration. We show here that pRb and p107, which are well known to regulate passage into S phase of the cell cycle and therefore control cell cycle exit, also regulate commissural axon tract formation in the developing brain. Following loss of pRb and p107 in the telencephalon, the axons of the corpus callosum and hippocampal commissure fail to cross the midline. The corticoseptal boundary is shifted ventro-caudally in double knockout brains and there are in the midline glial structures, which are well known to have axon guidance functions. In addition, commissural axons travelling through the intermediate zone towards the midline were highly disorganized. To understand why commissural axons fail to cross the midline, we examined expression of a panel of classic axon guidance molecules using in situ hybridization observed deregulation of a number of key molecules known to contribute to commissural axon crossing. This data indicates that the pRb family proteins are crucial for commissural plate development and regulate neuron maturation beyond control of proliferation. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.252