scholarly journals OTX2 non-cell autonomous activity regulates inner retinal function

2020 ◽  
Author(s):  
Raoul Torero-Ibad ◽  
Bilal Mazhar ◽  
Clémentine Vincent ◽  
Clémence Bernard ◽  
Julie Dégardin ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Transcription Factor ◽  
Bipolar Cells ◽  
Retinal Function ◽  
Single Chain ◽  
Inner Retina ◽  
Cell Functions ◽  
Conditional Expression ◽  
Autonomous Activity ◽  
Retinal Structure

AbstractOTX2 is a homeoprotein transcription factor expressed in photoreceptors and bipolar cells in the retina. OTX2, like many other homeoproteins, transfers between cells and exerts non-cell autonomous effects such as promoting survival of retinal ganglion cells that do not express the protein. Here we used a genetic approach to target extracellular OTX2 in the retina by conditional expression of a secreted single chain anti-OTX2 antibody. Compared to control mice, the expression of this antibody by Parvalbumin-expressing neurons in the retina is followed by a reduction in visual acuity in one-month-old mice with no alteration of the retinal structure or cell type number or aspect. A- and b-waves measured by electroretinogram were also indistinguishable from control mice, suggesting no functional deficit of photoreceptors and bipolar cells. Mice expressing the OTX2-neutralizing antibody did show a significant doubling in the flicker amplitude, consistent with a change in inner retinal function. Our results show that interfering in vivo with OTX2 non-cell autonomous activity in the postnatal retina leads to an alteration in inner retinal cell functions and causes a deficit in visual acuity.Significance statementOTX2 is a homeoprotein transcription factor expressed in retinal photoreceptors and bipolar cells. Although the Otx2 locus is silent in the inner retina, the protein is detected in cells of the ganglion cell layer consistent with the ability of this class of proteins to transfer between cells. We expressed a secreted single chain antibody (scFv) against OTX2 in the retina to neutralize extracellular OTX2. Antibody expression leads to reduced visual acuity with no change in retinal structure, or photoreceptor or bipolar physiology; however, activity in the inner retina was altered. Thus, interfering with OTX2 non-cell autonomous activity in postnatal retina alters inner retinal function and causes vision loss, highlighting the physiological value of homeoprotein direct non-cell autonomous signaling.

scholarly journals Progressive myoclonic epilepsy-associated geneKctd7regulates retinal neurovascular patterning and function

2019 ◽  
Author(s):  
Jonathan Alevy ◽  
Courtney A. Burger ◽  
Nicholas E. Albrecht ◽  
Danye Jiang ◽  
Melanie A. Samuel
Keyword(s):  
Bipolar Cells ◽  
Retinal Function ◽  
Myoclonic Epilepsy ◽  
Human Diseases ◽  
Inner Retina ◽  
Vascular Patterning ◽  
Neurovascular Interactions ◽  
Progressive Myoclonic Epilepsy ◽  
And Function ◽  
Neuron Function

AbstractNeuron function relies on and instructs the development and precise organization of neurovascular units that in turn support circuit activity. However, our understanding of the molecular cues that regulate this relationship remains sparse. Using a high-throughput screening pipeline, we recently identified several new regulators of vascular patterning. Among these was the potassium channel tetramerization domain-containing protein 7 (KCTD7). Mutations inKCTD7are associated with progressive myoclonic epilepsy, but how KCTD7 regulates neural development and function remains poorly understood. To begin to identify such mechanisms, we focus on mouse retina, a tractable part of the central nervous system that contains precisely ordered neuron subtypes supported by a trilaminar intravascular network. We find that deletion ofKctd7results in defective patterning of the adult retina vascular network, resulting in increased branching, vessel length, and lacunarity. These alterations reflect early and specific defects in vessel development, as emergence of the superficial and deep vascular layers were delayed. These defects are likely due to a role for Kctd7 in inner retina neurons. Kctd7 it is absent from vessels but present in neurons in the inner retina, and its deletion resulted in a corresponding increase in the number of bipolar cells in development and increased vessel branching in adults. These alterations were accompanied by retinal function deficits. Together, these data suggest that neuronal Kctd7 drives growth and patterning of the vasculature and suggest that neurovascular interactions may participate in the pathogenesis of KCTD7-related human diseases.Alevy et al. HighlightsKctd7 is required for normal retinal vascular organization and retinal function in adults.Deletion ofKctd7disrupts the emergence of the superficial and deep vessel layers.Kctd7 may impact vascular patterning through influencing neurons as it is expressed in and regulates bipolar cells.Kctd7 driven neurovascular interactions may participate in the pathogenesis of KCTD7-related human diseases.Lay SummaryNeuron function requires an organized vasculature to maintain brain health and prevent disease, but many neurovasculature regulatory genes remain unknown. Alevy et al. identify the progressive myoclonic epilepsy-associated geneKctd7as a key regulator of vascular development and retinal function. They further show that Kctd7 regulation of vessel patterning likely occurs downstream of its role in regulating the development or activity of specific neuron types. These data suggest that KCTD7-regulated neurovascular interactions may participate in the pathogenesis of associated human diseases.

scholarly journals Extracellular Pax6 regulates tangential Cajal-Retzius cell migration in the developing mouse neocortex

2018 ◽  
Author(s):  
H. Kaddour ◽  
E. Coppola ◽  
A. A. Di Nardo ◽  
A. Wizenmann ◽  
M. Volovitch ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Migration ◽  
Early Stage ◽  
Single Chain ◽  
Single Chain Antibody ◽  
Embryonic Mouse ◽  
Mouse Cortex ◽  
Autonomous Activity ◽  
Retzius Cell ◽  
Cortical Hem

AbstractThe embryonic mouse cortex displays a striking low caudo-medial and high rostro-lateral graded expression of the homeoprotein transcription factor Pax6, which presents both cell autonomous and direct non-cell autonomous activities. Through the genetic induction of anti-Pax6 single-chain antibody secretion, we have analyzed Pax6 non-cell autonomous activity on the migration of cortical hem- and septum-derived Cajal-Retzius (CR) neurons by live imaging of flat mount developing cerebral cortices. We observed that blocking extracellular Pax6 disrupts tangential CR cell migration patterns. We found a decrease in the distance travelled and changes both in directionality and in the depth at which CR cells migrate. Tracking of single CR cells in mutant cortices revealed that extracellular Pax6 neutralization enhances or reduces contact repulsion in medial and lateral regions, respectively. This study demonstrates that secreted Pax6 controls neuronal migration thus acting as a bona fide morphogen at an early stage of cerebral cortex development.Summary statementCajal-Retzius cell distribution in the embryonic cortex participates in determining the size and positioning of cortical areas. Here, Kaddour et al. establish that the direct non-cell autonomous activity of the Pax6 transcription factor regulates Cajal-Retzius cell migration.

Subcellular Localization and Complements of GABAA and GABAC Receptors on Bullfrog Retinal Bipolar Cells

2000 ◽  
Vol 84 (2) ◽  
pp. 666-676 ◽  
Author(s):  
Jiu-Lin Du ◽  
Xiong-Li Yang
Keyword(s):  
Subcellular Localization ◽  
Receptor Antagonist ◽  
Gaba Receptor ◽  
Drug Application ◽  
Bipolar Cells ◽  
Visual Signals ◽  
Receptor Subtypes ◽  
Inner Retina ◽  
Axon Terminals ◽  
Retinal Bipolar Cells

γ-Aminobutyric acid (GABA) receptors on retinal bipolar cells (BCs) are highly relevant to spatial and temporal integration of visual signals in the outer and inner retina. In the present work, subcellular localization and complements of GABAA and GABACreceptors on BCs were investigated by whole cell recordings and local drug application via multi-barreled puff pipettes in the bullfrog retinal slice preparation. Four types of the BCs (types 1–4) were identified morphologically by injection of Lucifer yellow. According to the ramification levels of the axon terminals and the responses of these cells to glutamate (or kainate) applied at their dendrites, types 1 and 2 of BCs were supposed to be off type, whereas types 3 and 4 of BCs might be on type. Bicuculline (BIC), a GABAA receptor antagonist, and imidazole-4-acetic acid (I4AA), a GABAC receptor antagonist, were used to distinguish GABA receptor-mediated responses. In all BCs tested, not only the axon terminals but also the dendrites showed high GABA sensitivity mediated by both GABAA and GABACreceptors. Subcellular localization and complements of GABAA and GABAC receptors at the dendrites and axon terminals were highly related to the dichotomy of offand on BCs. In the case of off BCs, GABAA receptors were rather evenly distributed at the dendrites and axon terminals, but GABAC receptors were predominantly expressed at the axon terminals. Moreover, the relative contribution of GABAC receptors to the axon terminals was prevalent over that of GABAA receptors, while the situation was reversed at the dendrites. In the case of on BCs, GABAA and GABAC receptors both preferred to be expressed at the axon terminals; relative contributions of these two GABA receptor subtypes to both the sites were comparable, while GABAC receptors were much less expressed than GABAA receptors. GABAA, but not GABAC receptors, were expressed clusteringly at axons of a population of BCs. In a minority of BCs, I4AA suppressed the GABAC responses at the dendrites, but not at the axon terminal, implying that the GABAC receptors at these two sites may be heterogeneous. Taken together, these results suggest that GABAA and GABAC receptors may play different roles in the outer and inner retina and the differential complements of the two receptors on off and on BCs may be closely related to physiological functions of these cells.

scholarly journals Downregulation of c-Jun Expression by Transcription Factor C/EBPα Is Critical for Granulocytic Lineage Commitment

2002 ◽  
Vol 22 (24) ◽  
pp. 8681-8694 ◽  
Author(s):  
Janki Rangatia ◽  
Rajani Kanth Vangala ◽  
Nicolai Treiber ◽  
Pu Zhang ◽  
Hanna Radomska ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Knockout Mouse ◽  
Leucine Zipper ◽  
Fetal Liver ◽  
Mrna Level ◽  
Monocytic Differentiation ◽  
Granulocytic Differentiation ◽  
Conditional Expression ◽  
Factor C ◽  
Transcription Factor Complex

ABSTRACT The transcription factor C/EBPα is crucial for the differentiation of granulocytes. Conditional expression of C/EBPα triggers neutrophilic differentiation, and C/EBPα can block 12-O-tetradecanoylphorbol-13-acetate-induced monocytic differentiation of bipotential myeloid cells. In C/EBPα knockout mice, no mature granulocytes are present. A dramatic increase of c-Jun mRNA in C/EBPα knockout mouse fetal liver was observed. c-Jun, a component of the AP-1 transcription factor complex and a coactivator of the transcription factor PU.1, is important for monocytic differentiation. Here we report that C/EBPα downregulates c-Jun expression to drive granulocytic differentiation. An ectopic increase of C/EBPα expression decreases the c-Jun mRNA level, and the human c-Jun promoter activity is downregulated eightfold in the presence of C/EBPα. C/EBPα and c-Jun interact through their leucine zipper domains, and this interaction prevents c-Jun from binding to DNA. This results in downregulation of c-Jun's capacity to autoregulate its own promoter through the proximal AP-1 site. Overexpression of c-Jun prevents C/EBPα-induced granulocytic differentiation. Thus, we propose a model in which C/EBPα needs to downregulate c-Jun expression and transactivation capacity for promoting granulocytic differentiation.

Brain-Protective Mechanisms of Transcription Factor NRF2: Toward a Common Strategy for Neurodegenerative Diseases

2021 ◽  
Vol 62 (1) ◽  
Author(s):  
Antonio Cuadrado
Keyword(s):  
Transcription Factor ◽  
Neurodegenerative Diseases ◽  
Brain Cell ◽  
Current Status ◽  
Annual Review ◽  
Publication Date ◽  
Related Factor ◽  
Protective Mechanisms ◽  
Cell Functions ◽  
Pass Through

Neurodegenerative diseases are characterized by the loss of homeostatic functions that control redox and energy metabolism, neuroinflammation, and proteostasis. The transcription factor nuclear factor erythroid 2–related factor 2 (NRF2) is a master controller of these functions, and its overall activity is compromised during aging and in these diseases. However, NRF2 can be activated pharmacologically and is now being considered a common therapeutic target. Many gaps still exist in our knowledge of the specific role that NRF2 plays in specialized brain cell functions or how these cells respond to the hallmarks of these diseases. This review discusses the relevance of NRF2 to several hallmark features of neurodegenerative diseases and the current status of pharmacological activators that might pass through the blood-brain barrier and provide a disease-modifying effect. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Functional and Structural Effects of Erythropoietin Subconjunctival Administration in Glaucomatous Animals

2018 ◽  
Vol 3 (2) ◽  
pp. 1-11 ◽  
Author(s):  
Ana Paula Resende ◽  
Serge G. Rosolen ◽  
Telmo Nunes ◽  
Berta São Braz ◽  
Esmeralda Delgado
Keyword(s):  
Neuroprotective Effect ◽  
Treated Group ◽  
Retinal Function ◽  
Function Evaluation ◽  
Control Group ◽  
Albino Rats ◽  
Subconjunctival Injection ◽  
Beneficial Effects ◽  
Structural Evaluation ◽  
Retinal Structure

Purpose: The present study aimed to assess functional and structural benefits of erythropoietin (EPO) when administered subconjunctivally in the retina of glaucomatous rats using electroretinography (ERG) and retinal thickness (RT) measurements. Methods: Glaucoma was experimentally induced in 26 Wistar Hannover albino rats. Animals were divided into 2 groups of 13 animals each: a treated group receiving a unique subconjunctival injection of 1,000 IU of EPO and a control group receiving a saline solution. In each group, 7 animals were used for retinal function evaluation (ERG) and 6 animals were used for retinal structural evaluation (histology). RT was measured, dorsally and ventrally, at 500 μm (RT1) and at 1,500 μm (RT2) from the optic nerve. Results: Retinal function evaluation: for both scotopic and photopic conditions, ERG wave amplitudes increased in the treated group. This increase was statistically significant (p < 0.05) in photopic conditions. Structural evaluation: for both locations RT1 and RT2, the retinas were significantly (p < 0.05) thicker in the treated group. Conclusion: Subconjunctival EPO administration showed beneficial effects both on retinal structure and on retinal function in induced glaucoma in albino rats. This neuroprotective effect should be applied in other animal species.

scholarly journals Unexpected Genetic Cause in Two Female Siblings with High Myopia and Reduced Visual Acuity

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
M. N. Preising ◽  
C. Friedburg ◽  
W. Bowl ◽  
B. Lorenz
Keyword(s):  
Visual Acuity ◽  
High Myopia ◽  
Autosomal Recessive ◽  
Electrical Coupling ◽  
Splice Site Mutation ◽  
Bipolar Cells ◽  
Night Vision ◽  
Site Mutation ◽  
Frequent Finding ◽  
Biallelic Mutations

In daily life, myopia is a frequent cause of reduced visual acuity (VA) due to missing or incomplete optical correction. While the genetic cause of high myopia itself is not well understood, a significant number of cases are secondary to hereditary malfunctions or degenerations of the retina. The mechanism by which this occurs remains yet unclear. Two female siblings, 4 y and 2 y, respectively, from a consanguineous Pakistani family were referred to our department for reduced VA and strabismus. Both girls were highly myopic and hence were further examined using standard clinical tests and electroretinography (ERG). The latter confirmed confounded electrical coupling of photoreceptors and bipolar cells. Further inquiry and testing confirmed a similar condition for the father including impaired night vision, reduced VA, photophobia, and an equally characteristic ERG. Findings in the mother were unremarkable. Subsequent genetic analysis of autosomal recessive and X-linked genes for congenital stationary night blindness (CSNB) revealed a novel homozygous splice site mutation in CACNA1F in the two girls transmitted from both the father and the mother. While in males the above clinical constellation is a frequent finding, this report, to the authors’ knowledge, is the first demonstrating biallelic mutations at the CACNA1F locus in females.

scholarly journals Morphology of Inner Retina in Rhesus Monkeys of Various Ages: A Comparative Study

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Jingfei Chen ◽  
Qihui Luo ◽  
Chao Huang ◽  
Wen Zeng ◽  
Ping Chen ◽  
...  
Keyword(s):  
Rhesus Monkeys ◽  
Morphological Structure ◽  
Plexiform Layer ◽  
Bipolar Cells ◽  
Growth Stages ◽  
Retinal Layer ◽  
Inner Plexiform Layer ◽  
Fiber Layer ◽  
Inner Retina ◽  
Biological Studies

Purpose. To investigate the changes of thickness in each layer, the morphology and density of inner neurons in rhesus monkeys’ retina at various growth stages, thus contribute useful data for further biological studies. Methods. The thickness of nerve fiber layer (NFL), the whole retina, inner plexiform layer (IPL), and outer plexiform layer (OPL) of rhesus monkeys at different ages were observed with hematoxylin and eosin (H&E) staining. The morphology and the density of inner neurons of rhesus monkey retina were detected by immunofluorescence. Results. The retina showed the well-known ten layers, the thickness of each retinal layer in rhesus monkeys at various ages increased rapidly after infant, and the retina was the thickest in adulthood, but the retinal thickness stop growing in senescent. Quantitative analysis showed that the maximum density of inner neurons was reached in adolescent, and then, the density of inner neurons decreased in adults and senescent retinas. And some changes in the morphology of rod bipolar cells have occurred in senescent. Conclusions. The structure of retina in rhesus monkeys is relatively immature at infant, and the inner retina of rhesus monkeys is mature in adolescent, while the thickness of each retinal layer was the most developed in the adult group. There was no significant change in senescence for the thickness of each retinal layer, but the number of the neurons in our study has a decreasing trend and the morphological structure has changed.

scholarly journals Conditional expression of PfAP2-G for controlled massive sexual conversion in Plasmodium falciparum

2020 ◽  
Vol 6 (24) ◽  
pp. eaaz5057 ◽  
Author(s):  
Oriol Llorà-Batlle ◽  
Lucas Michel-Todó ◽  
Kathrin Witmer ◽  
Haruka Toda ◽  
Carmen Fernández-Becerra ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Transcription Factor ◽  
Sexual Development ◽  
Malaria Parasite ◽  
Drug Susceptibility ◽  
Small Subset ◽  
Human Malaria Parasite ◽  
Conditional Expression ◽  
Sexual Stages

Malaria transmission requires that some asexual parasites convert into sexual forms termed gametocytes. The initial stages of sexual development, including sexually committed schizonts and sexual rings, remain poorly characterized, mainly because they are morphologically identical to their asexual counterparts and only a small subset of parasites undergo sexual development. Here, we describe a system for controlled sexual conversion in the human malaria parasite Plasmodium falciparum, based on conditional expression of the PfAP2-G transcription factor. Using this system, ~90 percent of the parasites converted into sexual forms upon induction, enabling the characterization of committed and early sexual stages without further purification. We characterized sexually committed schizonts and sexual rings at the transcriptomic and phenotypic levels, which revealed down-regulation of genes involved in solute transport upon sexual commitment, among other findings. The new inducible lines will facilitate the study of early sexual stages at additional levels, including multiomic characterization and drug susceptibility assays.

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