math5 is a murine orthologue of atonal, a bHLH proneural gene essential for the formation of photoreceptors and chordotonal organs in Drosophila. The expression of math5 coincides with the onset of retinal ganglion cell (RGC) differentiation. Targeted deletion of math5 blocks the initial differentiation of 80% of RGCs and results in an increase in differentiated amacrine cells. Furthermore, the absence of math5 abolishes the retinal expression of brn-3b and the formation of virtually all brn-3b-expressing RGCs. These results imply that math5 is a proneural gene essential for RGC differentiation and that math5 acts upstream to activate brn-3b-dependent differentiation processes in RGCs. The mammalian retina is the peripheral portion of the visual system containing six major neuronal cell types and one glial cell type organized in a laminar structure. The visual information process in the retina follows a general pathway from photoreceptors to bipolar cells to retinal ganglion cells (RGCs). Horizontal cells and amacrine cells act to mediate lateral interactions among photoreceptors, bipolar cells, and RGCs. The latter serve as the sole output neurons in the retina to send the visual information down the optic nerve to the rest of brain. Both birthdating experiments using 3 H-thymidine labeling and cell lineage analysis using retroviral and tracermediated approaches demonstrate that vertebrate retinal neurons are generated from common progenitors through sequential differentiation and ordered migration to form the laminar retinal structure (Cepko et al. 1996). Current models for retinal neuron differentiation suggest that the formation of a specific retinal neuron is determined by the intrinsic properties of the retinal progenitor and the extrinsic cues from the retinal environment (Cepko et al. 1996). Among the likely intrinsic factors, the basic helix-loop-helix (bHLH) class of proneural transcription factors appears to play an essential role in regulating the differentiation of retinal neurons (Cepko 1999). In Drosophila, expression of proneural genes of the achaete-scute complex (AS-C) and atonal (ato) in proneural clusters endow cells with neural competence (Jan and Jan 1993). Loss-of-function mutation of genes in AS-C causes the cells in the would-be proneural clusters to adopt epidermal fates rather than neuronal precursor fates. Conversely, gain-of-function mutations in the proneural genes leads to the ectopic formation of sensory neurons (Campuzano and Modolell 1992). The expression of ato is found in the optic furrow of the eye-antennal disc in addition to the ectodermal proneural clusters and sensory organ precursors, which give rise to the chordotonal organs. Deletion of ato causes the absence of the chordotonal organ and the lack of photoreceptors (Jarman et al. 1995), and the reduced expression of ato results in defects in axonal pathfinding of photoreceptors (White and Jarman 2000), suggesting that ato plays dual roles in determining neuronal potential and regulating specific neuronal differentiation...
Hypoxia-inducible factor (HIF) transcription factors respond to multiple environmental stressors, including hypoxia and hypoglycemia. We report that mice lacking the HIF family member HIF-2alpha (encoded by Epas1) have a syndrome of multiple-organ pathology, biochemical abnormalities and altered gene expression patterns. Histological and ultrastructural analyses showed retinopathy, hepatic steatosis, cardiac hypertrophy, skeletal myopathy, hypocellular bone marrow, azoospermia and mitochondrial abnormalities in these mice. Serum and urine metabolite studies showed hypoglycemia, lactic acidosis, altered Krebs cycle function and dysregulated fatty acid oxidation. Biochemical assays showed enhanced generation of reactive oxygen species (ROS), whereas molecular analyses indicated reduced expression of genes encoding the primary antioxidant enzymes (AOEs). Transfection analyses showed that HIF-2alpha could efficiently transactivate the promoters of the primary AOEs. Prenatal or postnatal treatment of Epas1-/- mice with a superoxide dismutase (SOD) mimetic reversed several aspects of the null phenotype. We propose a rheostat role for HIF-2alpha that allows for the maintenance of ROS as well as mitochondrial homeostasis.
In mice, all of the six retinal neuron types are generated from common multipotent retinal progenitors, and their differentiation from progenitors is regulated by both extrinsic and intrinsic factors. Previously, we showed that targeted deletion of the atonal (ato) homologue math5 blocked the differentiation of most retinal ganglion cells (RGCs), revealing an essential role for math5 in RGC differentiation. In this study, we used the Cre-loxP recombination system to trace the fate of math5-expressing cells in retina. Our results demonstrated that math5 expression was associated with the differentiation of multiple retinal neuron types, including RGCs, photoreceptor, horizontal, and amacrine cells, implying that math5 expression alone is not sufficient to determine the RGC fate. Math5 expression was restricted to postmitotic cells in developing retina, suggesting that cell fate commitment of retinal neurons occurs after the terminal mitosis. The insufficiency of and requirement for math5 in RGC differentiation indicates that, like ato in the development of Drosophila R8 photoreceptors, math5 plays a role in determining the RGC competence state of retinal progenitors and that additional positive and negative factors are required in determining RGC fate. Furthermore, we show that loss of Math5 function severely reduced the RGC expression of the transcription factors Brn-3b, Gfi-1, Isl-1, Isl-2, Nscl-1, Nscl-2, and RPF-1, suggesting that Math5 expression is required to activate a comprehensive transcription network of RGC differentiation.
IMPORTANCE Autoimmune epilepsy is an underrecognized condition, and its true incidence is unknown. Identifying patients with an underlying autoimmune origin is critical because these patients' condition may remain refractory to conventional antiseizure medications but may respond to immunotherapy.OBJECTIVE To determine the prevalence of neurological autoantibodies (Abs) among adult patients with epilepsy of unknown etiology. DESIGN, SETTING, AND PARTICIPANTSConsecutive patients presenting to neurology services with new-onset epilepsy or established epilepsy of unknown etiology were identified. Serum samples were tested for autoimmune encephalitis Abs as well as thyroperoxidase (TPO) and glutamic acid decarboxylase 65 (GAD65) Abs. An antibody prevalence in epilepsy (APE) score based on clinical characteristics was assigned prospectively. Data were collected from June 1, 2015, to June 1, 2016. MAIN OUTCOMES AND MEASURESPresence of neurological Abs. A score based on clinical characteristics was assigned to estimate the probability of seropositivity prior to antibody test results. Good seizure outcome was estimated on the basis of significant reduction of seizure frequency at the first follow-up or seizure freedom. RESULTSOf the 127 patients (68 males and 59 females) enrolled in the study, 15 were subsequently excluded after identification of an alternative diagnosis. Serum Abs suggesting a potential autoimmune etiology were detected in 39 (34.8%) cases. More than 1 Ab was detected in 7 patients (6.3%): 3 (2.7%) had TPO-Ab and voltage-gated potassium channel complex (VGKCc) Ab, 2 (1.
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