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M Elizabeth Ross

Publications and source records attributed to M Elizabeth Ross.

14 recordsLinked to original sources
PubMed2006

Parallel changes in metabolite and expression profiles in crooked-tail mutant and folate-reduced wild-type mice.

Anomalies in homocysteine (HCY) and folate metabolism are associated with common birth defects and adult diseases, several of which can be suppressed with dietary folate supplementation. Although supplementation reduces the occurrence and severity of neural tube defects (NTDs), many cases are resistant to these beneficial effects. The basis for variable response and biomarkers that predict responsiveness are unknown. Crooked-tail (Cd) mutant mice are an important model of folate-responsive NTDs. To identify features that are diagnostic for responsiveness versus resistance to dietary folate supplementation, we surveyed metabolite and expression levels in liver samples from folate-supplemented, folate-reduced and control diets in Cd mutant and wild-type adult females. Cd homozygotes had normal total homocysteine (tHcy) levels suggesting that folate suppresses NTDs through a mechanism that does not involve modulating serum tHcy levels. Instead, parallel changes in metabolite and expression profiles in folate-supplemented Cd/Cd homozygotes and folate-reduced+/+and Cd/+mice suggest that Crooked-tail homozygotes have a defect in the utilization of intracellular folate. Then, by combining these expression and metabolite profile results with published results for other models and their controls, two clusters were found, one of which included several folate-responsive NTD models and the other previously untested and presumably folate-resistant models. The predictive value of these profiles was verified by demonstrating that NTDs of Ski-/-mutant mice, whose profile suggested resistance to folate supplementation, were not suppressed with dietary folate supplementation. These results raise the possibility of using metabolite and expression profiles to distinguish folate-responsive and resistance adult females who are at risk for bearing fetuses with an NTD.

Animals↗
PubMed2006

Differences in cyclin D2 and D1 protein expression distinguish forebrain progenitor subsets.

Regulation of neural proliferation is an essential component of brain formation and is driven by both intrinsic cell cycle and extrinsic growth and trophic molecules. Among the cell cycle proteins, understanding of the relative roles of the G1-phase active cyclins D2 and D1 (cD2 and cD1) has been hampered by lack of data regarding their expression patterns. In this study, cD2 immunoreactivity was examined in the neocortex, ganglionic eminences/striatum, and hippocampal formation from embryonic day 12.5 until postnatal day 60 to more precisely characterize the expression of this protein during forebrain development. The localization of cD1 was also immunohistologically mapped for comparison. Throughout forebrain development, both overlapping and nonoverlapping protein expression of these cyclins suggests the presence of shared and unique cell cycle requirements for neurogenesis that distinguishes progenitor pools.

Animals↗
PubMed2005

Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronal motility.

Lis1 gene defects impair neuronal migration, causing the severe human brain malformation lissencephaly. Although much is known about its interactions with microtubules, microtubule-binding proteins such as CLIP-170, and with the dynein motor complex, the response of Lis1 to neuronal motility signals has not been elucidated. Lis1 deficiency is associated with deregulation of the Rho-family GTPases Cdc42, Rac1 and RhoA, and ensuing actin cytoskeletal defects, but the link between Lis1 and Rho GTPases remains unclear. We report here that calcium influx enhances neuronal motility through Lis1-dependent regulation of Rho GTPases. Lis1 promotes Cdc42 activation through interaction with the calcium sensitive GTPase scaffolding protein IQGAP1, maintaining the perimembrane localization of IQGAP1 and CLIP170 and thereby tethering microtubule ends to the cortical actin cytoskeleton. Lis1 thus is a key component of neuronal motility signal transduction that regulates the cytoskeleton by complexing with IQGAP1, active Cdc42 and CLIP-170 upon calcium influx.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2005

Crooked tail (Cd) model of human folate-responsive neural tube defects is mutated in Wnt coreceptor lipoprotein receptor-related protein 6.

A cranial neural tube defect in Crooked tail (Cd) mice is prevented with prenatal dietary folic acid Cd positional cloning reveals a missense mutation of a highly conserved amino acid in the low density lipoprotein receptor-related protein 6 (Lrp6), a coreceptor required for Wnt canonical signaling. Molecular modeling predicts that Lrp6(Cd) alters a hinge region of the second YWTD beta-propeller domain. Mutant LRP6 binds to Wnt and Dickkopf1 (Dkk1) but not Mesd1, and Dkk1 cannot antagonize Wnt in Cd/Cd cells, resulting in hyperactivity. NIH 3T3 cells transfected with a mutant Lrp6 plasmid resist Dkk1 antagonism much like Cd/+ cells, confirming the significance of the mutation. The Lrp6 mutation in Cd mice provides evidence for a functional connection between Wnt signaling and folate rescue of neural tube defects.

Amino Acid Sequence↗
PubMed2005

Involvement of kv1 potassium channels in spreading acidification and depression in the cerebellar cortex.

Spreading acidification and depression (SAD) is a form of propagated activity in the cerebellar cortex characterized by acidification and a transient depression in excitability. This study investigated the role of Kv1 potassium channels in SAD using neutral red, flavoprotein autofluorescence, and voltage-sensitive dye optical imaging in the mouse cerebellar cortex, in vivo. The probability of evoking SAD was greatly increased by blocking Kv1.1 as well as Kv1.2 potassium channels by their specific blockers dendrotoxin K (DTX-K) and tityustoxin (TsTX), respectively. DTX-K not only greatly lowered the threshold for evoking SAD but also resulted in multiple cycles of spread and spontaneous SAD. The occurrence of spontaneous SAD originating from spontaneous parallel fiber-like beams of activity suggests that blocking Kv1 channels increased parallel fiber excitability. This was confirmed by the generation of parallel fiber-like beams with the microinjection of glutamate into the upper molecular layer in the presence of DTX-K. The dramatic effects of DTX-K suggest a possible connection between SAD and episodic ataxia type 1 (EA1), a Kv1.1 potassium channelopathy. The threshold for evoking SAD was significantly lowered in the Kv1.1 heterozygous knockout mouse compared with wild-type littermates. Carbamazepine and acetazolamide, both effective in the treatment of EA1, significantly decreased the likelihood of evoking SAD. Blocking GABAergic neurotransmission did not alter the effectiveness of DTX-K. The cyclin D2 null mouse, which lacks cerebellar stellate cells, also exhibited SAD. Therefore blocking Kv1 potassium channels establishes the conditions needed to generate SAD. Furthermore, the results are consistent with the hypothesis that SAD may underlie the transient attacks of ataxia characterizing EA1.

Acetazolamide↗
PubMed2005

Obligatory role of inducible nitric oxide synthase in ischemic preconditioning.

Sublethal insults can induce a transient tolerance toward subsequent lethal ischemia, a phenomenon termed ischemic preconditioning (IPC). In the myocardium, nitric oxide derived from 'inducible' nitric oxide synthase (iNOS or NOS II) plays a critical role in the expression of IPC produced by sublethal ischemia. Here, we investigated whether iNOS is involved in IPC in brain. Ischemic preconditioning was produced in mice by three episodes of 1-min bilateral common carotid artery (BCCA) occlusion, each followed by 5 mins of reperfusion. After 24 h, mice underwent middle cerebral artery (MCA) occlusion for 20 mins. Intraischemic cerebral blood flow was monitored during both in BCCA and MCA occlusion (MCAO) by laser-Doppler flowmetry. Mice were killed 3 days after MCAO, and infarct volume was determined in thionine-stained sections. Infarct volume was significantly reduced 24 h after IPC (70%; P<0.05). Treatment with the iNOS inhibitor aminoguanidine (400 mg/kg), abolished the IPC-induced protection. Furthermore, IPC failed to induce ischemic tolerance in iNOS-null mice. In wild-type mice, IPC increased the resistance to Ca(2+)-mediated depolarization in isolated brain mitochondria. However, in iNOS-null mice IPC failed to induce such resistance. We conclude that iNOS is required for the full expression of IPC and that such effect is coupled to an increased resistance of mitochondria to injury. Thus, iNOS-derived nitric oxide, in addition to its deleterious effects on the late stages of ischemic brain damage, can also be beneficial by promoting ischemic tolerance through signaling, ultimately resulting in mitochondrial protection.

Animals↗
PubMed2004

G protein-coupled receptor-dependent development of human frontal cortex.

The mammalian cerebral cortex is characterized by complex patterns of anatomical and functional areas that differ markedly between species, but the molecular basis for this functional subdivision is largely unknown. Here, we show that mutations in GPR56, which encodes an orphan G protein-coupled receptor (GPCR) with a large extracellular domain, cause a human brain cortical malformation called bilateral frontoparietal polymicrogyria (BFPP). BFPP is characterized by disorganized cortical lamination that is most severe in frontal cortex. Our data suggest that GPCR signaling plays an essential role in regional development of human cerebral cortex.

Amino Acid Substitution↗
PubMed2004

Prostanoids, not reactive oxygen species, mediate COX-2-dependent neurotoxicity.

The prostaglandin synthesizing enzyme cyclooxygenase-2 (COX-2) has emerged as a critical pathogenic factor in brain diseases associated with activation of N-methyl-D-aspartate (NMDA) receptors, including stroke and neurodegenerative diseases. However, the COX-2 reaction products responsible for these deleterious effects have not been identified. In particular, the relative contribution to the neurotoxicity of COX-2-derived prostanoids and reactive oxygen species has not been defined. We found that the brain damage produced by direct injection of NMDA into the somatosensory cortex is attenuated by the COX-2 inhibitor NS-398 or in COX-2-null mice, but that the associated production of free radicals is not. Furthermore, COX-2 inhibition reduces the lesions even if the deleterious effects of free radicals are eliminated by the scavenger superoxide dismutase. The protection exerted by NS-398 is counteracted by a stable analog of prostaglandin E2. The findings directly implicate COX-2-derived prostanoids, rather then radicals, in the COX-2-dependent component of the damage mediated by NMDA receptors and strengthen the rationale for using COX-2 inhibitors in the treatment of neurological diseases associated with glutamate neurotoxicity.

Animals↗
PubMed2003

Disregulated RhoGTPases and actin cytoskeleton contribute to the migration defect in Lis1-deficient neurons.

Lissencephaly is a severe brain malformation caused by impaired neuronal migration. Lis1, a causative gene, functions in an evolutionarily conserved nuclear translocation pathway regulating dynein motor and microtubule dynamics. Whereas microtubule contributions to neuronal motility are incompletely understood, the actin cytoskeleton is essential for crawling cell movement of all cell types investigated. Lis1 haploinsufficiency is shown here to also result in reduced filamentous actin at the leading edge of migrating neurons, associated with upregulation of RhoA and downregulation of Rac1 and Cdc42 activity. Disruption of RhoA function through pharmacological inhibition of its effector kinase, p160ROCK, restores normal Rac1 and Cdc42 activity and rescues the motility defect in Lis1+/- neurons. These data indicate a previously unrecognized role for Lis1 protein in neuronal motility by promoting actin polymerization through the regulation of Rho GTPase activity. This effect of Lis1 on GTPases does not appear to occur through direct Lis1 binding of Rho, but could involve Lis1 effects on Rho modulatory proteins or on microtubule dynamics.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2003

L-Arginine increases ischemic injury in wild-type mice but not in iNOS-deficient mice.

Delayed administration of the nitric oxide precursor L-arginine increases brain injury in models of focal cerebral ischemia. We tested the hypothesis that L-arginine worsens the damage by acting as a substrate for inducible nitric oxide synthase (iNOS) and increasing the output of this enzyme. iNOS-null mice or wild-type littermates were treated with L-arginine (300 mg/kg; i.p, three times/day) starting 12 h after occlusion of the middle cerebral artery. Infarct volume was determined 96 h after ischemia. We found that L-arginine enlarges infarct volume in wild-type mice (+28+/-5% in neocortex) but not in iNOS-null mice. Thus, the worsening of ischemic damage produced by L-arginine depends on iNOS. The findings support the hypothesis that L-arginine worsens ischemic injury by increasing the catalytic output of iNOS and suggest that administration of L-arginine should be avoided in patients with acute stroke.

Animals↗
PubMed2003

Attenuation of activity-induced increases in cerebellar blood flow in mice lacking neuronal nitric oxide synthase.

We used mice deficient in neuronal nitric oxide (NO) synthase (nNOS) to specifically investigate the role of neuronal NO in the increase of cerebellar blood flow (BFcrb) produced by neural activation. Crus II, a region of the cerebellar cortex that receives trigeminal sensory afferents, was activated by low-intensity stimulation of the upper lip (5-25 V, 4-16 Hz) in anesthetized mice. BFcrb was recorded in Crus II by using a laser-Doppler flow probe. In wild-type mice, upper lip stimulation increased BFcrb in the Crus II by 28 +/- 3% (25 V, 10 Hz, n = 6). The rise in BFcrb was attenuated by 73 +/- 3% in nNOS-/- mice (P < 0.05, n = 6). The increases in BFcrb produced by superfusion of Crus II with glutamate or by systemic administration of harmaline were also attenuated in nNOS-/- mice (P < 0.05). In contrast, the increases in BFcrb produced by topical superfusion of Crus II with acetylcholine or adenosine and the increase in BFcrb produced by hypercapnia were not affected (P > 0.05). The field potentials evoked in the Crus II by upper lip stimulation did not differ between wild-type and nNOS-null mice. These data provide the first nonpharmacological evidence that nNOS-derived NO is a critical link between glutamatergic synaptic activity and blood flow in the activated cerebellum.

Acetylcholine↗
PubMed2002

Interferon regulatory factor-1 immunoreactivity in neurons and inflammatory cells following ischemic stroke in rodents and humans.

Interferon regulatory factor-1 (IRF-1), a transcription factor that controls the expression of genes related to inflammation and injury, may be involved in the mechanisms of cerebral ischemia. In this study, we used immunohistochemistry to determine whether IRF-1 protein is up-regulated after cerebral ischemia, and to define the identity of the cells that express IRF-1 in the postischemic brain. In mice, IRF-1 immunoreactivity was present in intravascular neutrophils 24 h after middle cerebral artery occlusion. At 96 h, immunoreactivity was observed in neutrophils infiltrating the ischemic tissue and in neurons at the outer border of the ischemic territory. IRF-1 immunoreactivity was also found in neurons and inflammatory cells in the brain of patients who died 1-2 days after ischemic stroke. The neuronal expression of IRF-1, in conjunction with the finding that IRF-1 deletion is beneficial to the post-ischemic brain, suggests that expression of IRF-1-dependent genes in neurons plays a role in ischemic neuronal death.

Aged↗
PubMed2002

Brain malformations, epilepsy, and infantile spasms.

The models of cortical dysplasia discussed earlier--the Lis1 knockout, the MAM-induced cobblestone LIS, the spontaneous tish mutant, and focal freeze injury-induced PMG--illustrate several important insights into epileptogenesis in malformed brain. First, the appearance of epilepsy varies according to the pathogenesis of the dysplasia and may well depend more on the intrinsic properties of the neurons in these models rather than on the disturbed position of the cells. This is supported by models such as the reeler mouse, in which the dysfunctional extracellular matrix molecule leads to a form of lissencephaly in mouse and human, but there is a far less impressive association with seizures than for LIS1 mutations. However, Lis1 and Dex mutations that appear to affect the cytoskeleton and perhaps intracellular protein trafficking are frequently associated with infantile spasms and epilepsy. Second, the possible mechanisms of epileptogenesis in these models include (a) a loss of subsets of neurons, (b) altered neurotransmitter release, (c) differences in neurotransmitter receptor levels and changes in receptor subunit composition, (d) altered neurite density and/or synaptogenesis, (e) changed membrane properties (e.g., altered voltage-gated channels), (f) altered cell morphology (neuronal differentiation), and (g) effects on cytoskeletal function. Finally, it is important to note that the "generator" of excitability in affected brain may be within the heterotopia or in the normotopic cortex. As additional genetic models come to light and the ability to distinguish their clinical counterparts improves, more individually tailored therapies, including standards for surgical interventions, will surely evolve.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗