Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Either phencyclidine hydrochloride (PCP) (5, 10, or 20 mg/kg) or saline was administered by subcutaneous injection to gravid CF-1 mice during either Mid (E6-15) or Late (E12-18) gestation. A nontreated control group (UTC) was left undisturbed during pregnancy. All treated and control litters were fostered at birth to untreated dams. Although postnatal challenge of PCP increased motor activity and ataxia in a dose-related manner, prenatal PCP had no effect on postnatal motor activity, ataxia or 3H-PCP binding. However, treatment period did have a significant effect on ataxia and 3H-PCP binding. In response to challenge doses of 5.0 and 7.5 mg/kg PCP, ataxia scores of the Late gestation offspring were significantly greater than the UTC offspring which in turn were significantly greater than the ataxia scores of the Mid gestation group. The results are discussed in relation to other animal and clinical reports of prenatal PCP exposure.
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PMID:Effects of prenatal phencyclidine on 3H-PCP binding and PCP-induced motor activity and ataxia. 279 92

To address the role of N-myc in neurogenesis and in nervous system tumors, it was conditionally disrupted in neuronal progenitor cells (NPCs) with a nestin-Cre transgene. Null mice display ataxia, behavioral abnormalities, and tremors that correlate with a twofold decrease in brain mass that disproportionately affects the cerebellum (sixfold reduced in mass) and the cerebral cortex, both of which show signs of disorganization. In control mice at E12.5, we observe a domain of high N-Myc protein expression in the rapidly proliferating cerebellar primordium. Targeted deletion of N-myc results in severely compromised proliferation as shown by a striking decrease in S phase and mitotic cells as well as in cells expressing the Myc target gene cyclin D2, whereas apoptosis is unaffected. Null progenitor cells also have comparatively high levels of the cdk inhibitors p27(Kip1) and p18(Ink4c), whereas p15(Ink4b), p21(Cip1), and p19(Ink4d) levels are unaffected. Many null progenitors also exhibit altered nuclear morphology and size. In addition, loss of N-myc disrupts neuronal differentiation as evidenced by ectopic staining of the neuron specific marker betaTUBIII in the cerebrum. Furthermore, in progenitor cell cultures derived from null embryonic brain, we observe a dramatic increase in neuronal differentiation compared with controls. Thus, N-myc is essential for normal neurogenesis, regulating NPC proliferation, differentiation, and nuclear size. Its effects on proliferation and differentiation appear due, at least in part, to down-regulation of a specific subset of cyclin-dependent kinase inhibitors.
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PMID:N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. 1238 68

Mental retardation (MR) affects up to two percent of the population and is usually accompanied by impaired learning and memory. MR is frequently associated with mutations of genes involved in Rho signal transduction cascades. Rho signal transduction pathways regulate axonal and dendritic growth during embryonic development and morphological adaptations of dendritic spines during synaptic plasticity in adult neurons. The MEGAP/SRGAP3 protein is part of the Rho signal transduction cascades. Mutation of MEGAP (Mental disorder associated GTPase-activating protein) gene is present in some patients who have MR, ataxia and monosomy for the distal portion of the short arm of chromosome 3. Here, we investigated the pattern of mouse MEGAP mRNA expression during embryonic development. Mouse embryos and brain sections from stage E10 to adults were analysed by in-situ hybridisation for MEGAP transcript in whole-mount and in brain sections. We demonstrate here robust expression of MEGAP mRNA in the whole central nervous system of E10 embryos. At E12, we also detected MEGAP in dorsal root ganglia. This pattern narrows in adult animals into an expression mainly in hippocampus and cortex. Our findings support the presumed role of MEGAP in Rho-associated MR.
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PMID:Expression of MEGAP mRNA during embryonic development. 1834 2

Development of the cerebellum involves a coordinated program of neuronal process outgrowth and migration resulting in a foliated structure that plays a key role in motor function. Neuron navigator 2 (Nav2) is a cytoskeletal-interacting protein that functions in neurite outgrowth and axonal elongation. Herein we show that hypomorphic mutant mice lacking the full-length Nav2 transcript exhibit ataxia and defects in cerebellar development. At embryonic day (E)17.5, the mutant cerebellum is reduced in size and exhibits defects in vermal foliation. Reduction in cell proliferation at early times (E12.5 and E14.5) may contribute to this size reduction. The full-length Nav2 transcript is expressed in the premigratory zone of the external granule layer (EGL). Granule cells in the germinal zone of the EGL appear to proliferate normally, however, due to the reduction in cerebellar circumference there are fewer total BrdU-labeled granule cells in the mutants, and these fail to migrate normally toward the interior of the cerebellum. In Nav2 hypomorphs, fewer granule cells migrate out of cerebellar EGL explants and neurite outgrowth from both explants and isolated external granule cell cultures is reduced. This suggests that the formation of parallel axon fibers and neuronal migration is disrupted in Nav2 mutants. This work supports an essential role for full-length Nav2 in cerebellar development, including axonal elongation and migration of the EGL neurons.
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PMID:Nav2 hypomorphic mutant mice are ataxic and exhibit abnormalities in cerebellar development. 2141 14

PDSS2 is a gene that encodes one of the two subunits of trans-prenyl diphosphate synthase that is essential for ubiquinone biosynthesis. It is known that mutations in PDSS2 can cause primary ubiquinone deficiency in humans and a similar disease in mice. Cerebellum is the most often affected organ in ubiquinone deficiency, and cerebellar atrophy has been diagnosed in many infants with this disease. In this study, two Pdss2 conditional knockout mouse lines directed by Pax2-cre and Pcp2-cre were generated to investigate the effect of ubiquinone deficiency on cerebellum during embryonic development and in adulthood, respectively. The Pdss2(f/-); Pax2-cre mouse recapitulates some symptoms of ubiquinone deficiency in infants, including severe cerebellum hypoplasia and lipid accumulation in skeletal muscles at birth. During early cerebellum development (E12.5-14.5), Pdss2 knockout initially causes the delay of radial glial cell growth and neuron progenitor migration, so the growth of mutant cerebellum is retarded. During later development (E15.5-P0), increased ectopic apoptosis of neuroblasts and impaired cell proliferation result in the progression of cerebellum hypoplasia in the mutant. Thus, the mutant cerebellum contains fewer neurons at birth, and the cells are disorganized. The developmental defect of mutant cerebellum does not result from reduced Fgf8 expression before E12.5. Electron microscopy reveals mitochondrial defects and increased autophagic-like vacuolization that may arise in response to abnormal mitochondria in the mutant cerebellum. Nevertheless, the mutant mice die soon after birth probably due to cleft palate and micrognathia, which may result from Pdss2 knockout caused by ectopic Pax2-cre expression in the first branchial arch. On the other hand, the Pdss2(f/-); Pcp2-cre mouse is healthy at birth but gradually loses cerebellar Purkinje cells and develops ataxia-like symptoms at 9.5 months; thus this conditional knockout mouse may serve as a model for ubiquinone deficiency in adult patients. In conclusion, this study provides two mouse models of Pdss2 based ubiquinone deficiency. During cerebellum development, Pdss2 knockout results in severe cerebellum hypoplasia by impairing cell migration and eliciting ectopic apoptosis, whereas Pdss2 knockout in Purkinje cells at postnatal stages leads to the development of cerebellar ataxia.
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PMID:Cerebellar defects in Pdss2 conditional knockout mice during embryonic development and in adulthood. 2187 65