Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A incidência de doenças renais crônicas está aumentando no mundo, e há uma grande necessidade de identificar as terapias capazes de deter ou reduzir a progressão da doença. Há crescente evidência clínica e experimental de que as estatinas poderiam desempenhar um papel terapêutico. Recentes estudos clínicos e experimentais têm mostrado que as estatinas têm "efeitos pleiotrópicos", além da modulação lipídica. Estudos têm avaliado os efeitos das estatinas sobre a progressão da doença renal crônica, mas os resultados são controversos. Estudos ultra-estruturais em humanos e em ratos demonstraram a presença de junções GAP dentro de todas as células do glomérulo e os podocitos demonstraram conter principalmente conexina-43 (Cx-43). O presente estudo tem como objetivo observar os efeitos da rosuvastatina na estrutura e ultra-estrutura renal e a expressão glomerular de Cx-43 em ratos normotensos (WKY) e em ratos espontaneamente hipertensos (SHR). O foco do estudo foi avaliar os efeitos pleiotrópicos da rosuvastatina em rins de animais hipertensos normocolesterolêmicos. Os ratos foram divididos aleatoriamente em quatro grupos: WKY-C: animais normotensos que não receberam rosuvastatina; WKY-ROS: animais normotensos que receberam rosuvastatina 20mg/kg/dia por gavagem orogástrica; SHR-C: animais hipertensos que não receberam rosuvastatina; SHR-ROS: animais hipertensos que receberam rosuvastatina, como descrito no grupo WKY-ROS. Os animais dos grupos SHR-C e SHR-ROS apresentaram níveis de pressão arterial maiores que os animais dos grupos WKY-C e WKY-Ros. A massa corporal dos grupos de animais não diferiram significativamente durante o experimento. Não houve diferença nos níveis sanguíneos de uréia, creatinina, ácido úrico e creatinafosfoquinase entre os animas dos grupos estudados. No entanto, houve um aumento da excreção de proteína de 24 horas nos animais do grupo SHR-C. Houve um aumento na área capsular nos animais do grupo SHR-C. Por microscopia eletrônica de transmissão observou-se que nos animais SHR-C a barreira de filtração glomerular, o diafragma de fenda e os podócitos estão alterados exibindo os vacúolos nos podócitos e pedicelos mais curtos e mais espessos. Por microscopia eletrônica de varredura, os animais SHR-C exibiram pedicelos mais afilados, curtos e tortuosos. Um aumento da imunofluorescência para Cx-43 foi observada em células epiteliais viscerais dos glomérulos dos animais do grupo WKY-ROS e nas células parietais e viscerais dos glomérulos dos animais do grupo SHR-ROS, se comparado com os grupos WKY-C e SHR-C. Em conclusão, podemos supor que o efeito pleiotrópico renal da rosuvastatina pode ser uma ferramenta terapêutica para melhorar a estrutura e conseqüentemente a função renal em indivíduos hipertensos. / The incidence of chronic renal diseases is increasing worldwide, and there is a great need to identify therapies capable of arresting or reducing disease progression. There is growing clinical and experimental evidence that statins could play a therapeutic role. Recent clinical and experimental studies have shown that statins have pleiotropic effects, besides modulating lipid. Studies have evaluated the effects of statins on the progression of chronic kidney disease but the results are controversial. Ultrastructural studies in both humans and rats have shown the presence of gap junctions within all the cells of the glomerulus and podocytes have been found to contain primarily connexin-43 (Cx-43). The present study aims to observe the effects of rosuvastatin on structural and ultrastructural renal morphology and on glomerular Cx-43 expression in normotensive rats and SHR. The focus of the study was to evaluate the pleiotropic action of rosuvastatin upon kidney in hypertensive normocholesterolemic animals. Rats were randomly allocated into four groups (n=8 each): WKY-C: normotensive animals no receiving rosuvastatin; WKY-ROS: normotensive animals receiving rosuvastatin 20mg/kg/day by orogastric gavage; SHR-C: hypertensive animals no receiving rosuvastatin; SHR-ROS: hypertensive animals receiving rosuvastatin, as described for WKY-ROS group. The SHR-C and SHR-ROS had increased blood pressure levels. The body mass of the animal groups did not differ significantly throughout the experiment. There were no differences in blood urea, creatinine, uric acid and CPK levels between the groups. However, there was an increasing of 24 hour protein excretion in SHR-C. There was an increasing in capsular area in SHR-C. By transmission electron microscopy it was observed that in SHR-C animals the glomerular filtration barrier, the slit diaphragm and the podocyte foot processes are altered exhibiting the vacuoles in the podocytes and the pedicels are shorter and thicker. By scanning electron microscopy the SHR-C animals shows the thinner, shorter and more tortuous pedicels. Increased Cx-43 immunofluorescence was observed at visceral epithelial cells of the glomeruli of WKY-ROS and at parietal and visceral epithelial cells of the glomeruli SHR-ROS groups if compared with WKY-C and SHR-C groups. In conclusion, we hypothesize that renal pleiotropic effect of rosuvastatin can be a therapeutic tool for improving kidney ultrastructure and, consequently, renal function in hypertensive individuals.

Light entering the eye is transformed by the retina into electrical signals. Extensive processing takes place in the retina before these signals are transmitted to the brain. Beginning in the outer retina, light-evoked electrical signals are distributed into parallel pathways specialized for different visual tasks, such as the detection of dark vs. bright ambient light, the onset or offset of light, and the direction of stimulus motion. Pathway diversity is a consequence of cell type diversity, differential cell connectivity, synapse organization, receptor expression, or any combination thereof. Cell connectivity itself can be accomplished through excitatory or inhibitory chemical synapses, or electrical coupling via gap junctions. Gap junctions are further specialized based on the expression of different connexin subunit isoforms. In aggregate, this diversity gives rise to ganglion cells with highly specialized functions, including ON and/or OFF responses, contrast-tuning and direction-selectivity (DS). The directionally-selective circuit, a circuit specialized for the encoding of stimulus motion, makes use of many of these circuit specializations. Bipolar cells, in response to glutamate release from cone photoreceptors, provide highly-sensitive glutamatergic input to amacrine cells and DS ganglion cells (DSGCs) in this circuit, while amacrine cells provide cholinergic and directionally-tuned GABAergic input to DSGCs. One population of DSGCs also transmit signals laterally to one another via gap junctions. Thus numerous specializations in bipolar cells, amacrine cells and ganglion cells endow DSGCs with their unique encoding abilities. In Chapters 2 and 3 of this dissertation I focus on synchronized firing between gap junction-coupled DSGCs. sDSGCs exhibit fine-scale correlations, with action potentials in an sDSGC more likely within ~2ms of action potential firing in a coupled neighbour. I first characterize electrical coupling of DSGCs through the identification of the molecular composition of DSGC gap junctions (Chapter 2). Physiological and immunohistochemical methods allowed me to demonstrate an important role for connexin 36 subunits in DSGC electrical coupling. Next (Chapter 3) I investigate the sub-cellular mechanisms underlying neuronal correlations between electrically coupled DSGCs. Using paired recordings, I show that chemical input (from bipolar cells and amacrine cells), electrical input (from gap junctions), and Na+ channel activity in DSGC dendrites underlie the generation of correlated spiking activity. While a common feature of electrically coupled networks, the mechanisms underlying correlations were previously unclear. In Chapter 4 I focus on the mechanisms within the DS circuit that endow these neurons with impressive sensitivity to stimulus contrast. Using physiological and pharmacological methods I first assess the relative contrast sensitivity of ganglion cells and starburst amacrine cells (SACs) in the DS circuit. The sensitivity of DSGC and SAC excitatory currents to antagonists of Na+ channels suggests an important role for these channels in amplifying low contrast responses and other weak inputs to the circuit. This role is later attributed to the differential expression of voltage-gated Na+ channels in specific bipolar cell populations. In aggregate, this dissertation describes several novel circuit mechanisms within the well-studied DS circuit. I also provide specific roles for such specializations in visual coding. / Graduate

Kainic acid induced excitotoxicity causes pyramidal cell death in the CA3a/b region of the hippocampus. Electrical synapses, gap junctional communication, and single membrane channels in non-junctional membranes (hemichannels) composed of connexin36 (Cx36) have been implicated in both seizure propagation and the spread of excitotoxic cell death. In rats, Cx36 protein is expressed by pyramidal neurons. Localization of protein in mouse, however, is highly controversial. Expression is reported to be restricted to hippocampal interneurons yet the same excitotoxic mechanisms (electrical and metabolic coupling between pyramidal neurons) are invoked to explain the role of Cx36 in excitotoxic pyramidal loss in murine brain. To address this controversy, I show by confocal immunofluorescence and in situ hybridization that Cx36 protein expression is restricted to interneurons and microglia in murine hippocampus and is not expressed by, or is below level of detection in pyramidal neurons. Using behavioural and electrophysiological measures, seizure propagation was found to be moderately enhanced in the absence of Cx36 likely due to the loss of interneuron-mediated synchronous inhibition of the pyramidal cells. Further, CA3a/b neurons die post kainic acid injury in the presence of Cx36 but are protected in Cx36-/- mice. When delayed excitotoxic cell death is maximal, Cx36 is primarily expressed by activated microglia as demonstrated by confocal immunofluorescence, in situ hybridization, and Western blotting. These activated microglia are located in the direct vicinity of, and surrounding cells in the damaged Ca3a/b region. Finally, I show that loss of Cx36 from activated microglia in mice is sufficient to prevent excitotoxic cell death in the CA3a/b with surviving neurons functional as assessed by both electrophysiological and behavioural measures. Together, these data identify a new mechanism of excitotoxic injury, mediated by neuronal-glial interactions, and dependent on microglial Cx36 expression.

Le système de conduction ventriculaire (SCV) est responsable de la propagation rapide de l’activité électrique dans le cœur. Il est composé du faisceau de His, des branches droite et gauche, et des fibres de Purkinje. 1) Le développement du SCV a été étudié par l’utilisation de souris transgéniques exprimant la recombinase Cre inductible, insérée par recombinaison homologue au locus du gène de la connexine-40 (Cx40). Ce gène code pour une protéine exprimée dans les trabécules ventriculaires et le SCV. La recombinaison est observée uniquement dans les cellules exprimant la Cx40 et leur descendance. Mes résultats révèlent une restriction progressive du destin des trabécules Cx40-positives en cardiomyocytes conducteurs. Les progéniteurs Cx40-positifs participent à la formation du myocarde contractile et du SCV de E10.5 à E14.5 ; alors qu’ils ne donnent que des cardiomyocytes conducteurs après E16.5. 2) L’analyse du SCV a été étudiée dans un modèle de malformation cardiaque congénitale. Le mutant Tbx1-/-, modèle du syndrome de DiGeorge humain, présente une communication inter-ventriculaire. Des défauts morphologiques du SCV sont détectés chez ces mutants : absence de branche droite et un faisceau de His moins compacté. Ceux-ci sont corrélés avec des défauts de conduction. Le phénotype observé ne résulte pas d’un défaut d’activation du programme génique à l’origine de l’établissement du SCV ; mais semble dû à la présence de la communication inter-ventriculaire qui empêcherait les cellules progénitrices du SCV de rejoindre le sommet du septum inter-ventriculaire. / The ventricular conduction system (VCS) is responsible for the rapid propagation of electrical activity in the heart. The VCS is composed of the His bundle, the left and right bundle branches, and the peripheral Purkinje fibers. 1) The development of the VCS has been studied by using transgenic mice expressing the inducible Cre recombinase, introduced by homologous recombination at the locus of gene of connexin-40 (Cx40). Cx40 encodes for a protein expressing in the ventricular trabeculae and the VCS. The recombination is observed in the cells expressing Cx40 and in their descendants. My results suggest a progressive restriction of the fate of Cx40-positive trabeculae in conductive cardiomyocytes. Cx40-positive progenitors give rise to the formation of the compact myocardium and of the VCS when they are induced between E10.5-E14.5; while they participate only in the cardiomyocytes of VCS after E16.5. 2) The analysis of the VCS has been studied in a model of congenital heart malformation. The mutant Tbx1-/-, model of the DiGeorge syndrome, present a ventricular septal defect. Morphological defects of the VCS are found in Tbx1-/- hearts: an absence of right bundle branch and a non-compacted His bundle; which are correlated with functional defect. The phenotype observed in these mutants does not result from a defect of the activation in the genetic program being at the origin of the establishment in the VCS, but seems to be explain by the presence of a large ventricular septal defect, because it could block the progression of the progenitors of the VCS along the crest of the inter-ventricular septum.

No description available.

No description available.

The aim of the two studies presented here was to evaluate the effects of cocaine and mefloquine (MFQ) on γ-aminobutyric acid (GABA) and dopamine (DA) neurons in the ventral tegmental area (VTA). Cocaine: In vivo, lower doses of intravenous cocaine (0.25-0.5 mg/kg), or methamphetamine (METH), enhanced VTA GABA neuron firing rate via D2/D5 receptor activation. Higher cocaine doses (1.0-2.0 mg/kg) inhibited their firing rate. Cocaine and lidocaine inhibited the firing rate and spike discharges induced by stimulation of the internal capsule (ICPSDs) at dose levels 0.25-2 mg/kg (IC50 1.2 mg/kg), but neither DA nor METH reduced ICPSDs. In VTA GABA neurons in vitro, cocaine reduced (IC50 13 µM) current-evoked spikes and sodium currents in a use-dependent manner. In VTA DA neurons, cocaine reduced IPSCs (IC50 13 µM), increased IPSC paired-pulse facilitation, and decreased sIPSC frequency, without affecting mIPSC frequency or amplitude. These findings suggest cocaine reduces activity-dependent GABA release on DA neurons in the VTA, and that cocaine's use-dependent blockade of VTA GABA neuron voltage-sensitive sodium channels (VSSCs) may synergize with its DAT inhibiting properties to enhance mesolimbic DA transmission implicated in cocaine reinforcement. Mefloquine: Mefloquine (MFQ) is an anti-malarial agent, Connexin-36 (Cx36) gap junction blocker, 5-HT3 antagonist, and calcium ionophore. Mounting evidence of a Cx36-mediated VTA GABA neuron syncytium suggests MFQ-related dysphoria may attribute to its gap junction blocking effects on VTA synaptic homeostasis. We observed that MFQ (25 µM) increased DA neuron spontaneous IPSC frequency 6 fold, and mIPSC 3 fold. Carbenoxolone (CBX, 100 µM) only increased sIPSC frequency 2 fold, and did not affect DA mIPSC frequency. Ondansetron did not mimic MFQ. Additionally, MFQ did not affect VTA DA evoked IPSC paired pulse ratio (PPR). However, Mefloquine did induce a 3.5 fold increase in bath-applied GABA current. Remarkably, MFQ did not affect VTA GABA neuron inhibition. At VTA DA neuron excitatory synapses MFQ increased sEPSC frequency in-part due to an increase in the AMPA/NMDA ratio. These finding suggest MFQ alters VTA synapses differentially depending on neuron and synapse type, and that these alterations appear to involve MFQ's gap junction blocking and calcium ionophore actions.

Le récepteur nucléaire Nr5a2 est exprimé dans l’ovaire, plus spécifiquement dans les cellules de granulosa et lutéales. Une déplétion conditionnelle de Nr5a2 dans les cellules de granulosa au stade de follicule primaire par croisement de souris Nr5a2-flox et Amhr2-Cre (Nr5a2f/fAmhr2Cre/+) génère des problèmes au niveau de l’expansion du cumulus, de l’ovulation et de la lutéinisation. Ainsi, nous estimons que Nr5a2 régule les connexions intercellulaires dans le follicule ovarien via la connexine 43 (Cx43), une protéine de jonction impliquée dans l’expansion du cumulus. Le premier objectif de l’étude était de déterminer si l’absence d’expansion du cumulus chez les souris Amhr2Cre-cKO est liée à l’absence de communication intercellulaire adéquate entre les cellules de granulosa et de cumulus dans les follicules préovulatoires. À cette fin, des ovaires de souris immatures Amhr2Cre-cKO et non transgéniques ont été prélevés (n=3) après un traitement de superstimulation utilisant les gonadotropines eCG suivie de hCG afin d’induire l’ovulation. Nous avons ainsi démontré, par RT-PCR, une sous-expression de Cx43 avant et au moment du stimulus ovulatoire (0 h et 2 h) chez le groupe Amhr2Cre-cKO (P<0.01), ce qui pourrait mener à un problème dans l’acquisition de la compétence développementale de l’oocyte. D’un autre côté, au moment de l’ovulation (12 h), l’ARNm de Cx43 est surexprimé dans le groupe Amhr2Cre-cKO, ce qui pourrait prévenir les cellules du cumulus de se détacher l’une de l’autre. Nous avons ainsi conclu que Cx43 est un gène sous le contrôle de Nr5a2 et qu’une régulation erronée de ce gène est une cause possible du problème d’expansion du cumulus chez les souris Amhr2Cre-cKO. Afin d’examiner le rôle de Nr5a2 dans l’ovulation et la lutéinisation à différents stades de la maturation folliculaire, nous suggérons que Nr5a2 module la séquence temporelle des événements menant à l’ovulation. En croisant des souris Nr5a2-flox et Cyp19-Cre (Nr5a2f/fCyp19Cre/+), l’expression de Nr5a2 a été interrompue dans les cellules de granulosa des follicules antraux et préovulatoires. Aucune portée n’a été obtenue de ces souris (n=4) durant un essai d’accouplement de 6 mois. Chez les souris Cyp19Cre-cKO on remarque la présence de structures s’apparentant à des cellules de type lutéales et les femelles âgées d’un an présentent des kystes folliculaires hémorragiques et une hypertrophie de l’épithélium en surface de l’ovaire. Les deux modèles transgéniques démontrent donc une absence de l’expansion du cumulus et de l’ovulation. En conclusion, Nr5a2 semble réguler différemment la folliculogenèse et l’ovulation dans les cellules de granulosa des follicules primaires et antraux. / The nuclear receptor Nr5a2 is expressed in the ovary, exclusively in granulosa and luteal cells. Conditional disruption of Nr5a2 in granulosa cells beginning with primary follicles by means of Nr5a2-floxed and Amhr2-Cre mice (Nr5a2f/fAmhr2Cre/+) results in failure in cumulus expansion, ovulation and luteinization. We hypothesize that Nr5a2 regulates intercellular connections in ovarian follicles through connexin 43 (Cx43), a gap-junctional protein related to cumulus expansion. The first objective of this study was to determine whether the lack of cumulus expansion in Amhr2Cre-cKO mice is related to the absence of normal cell-to-cell communication in cumulus/granulosa cells of preovulatory follicles. To address this, immature ovaries of Amhr2Cre-cKO and non-transgenic littermates mice were collected (n=3) after superstimulation to induce follicle development and ovulation. Using RT-PCR, the Cx43 mRNA levels were shown to be downregulated prior to and at the time of the ovulatory stimulus (0 h and 2 h) in the Amhr2Cre-cKO group (P<0.01), which may lead to the failure in the acquisition of oocyte developmental competence. On the other hand, by the time of ovulation (12 h), mRNA levels of Cx43 are upregulated in Amhr2Cre-cKO group, which may prevent the cumulus cells to detach one from another. We conclude that Cx43 is one of the downstream genes under Nr5a2 control and its dysregulation can be one reason for the defect in cumulus expansion in Amhr2Cre-cKO females. To examine the role of Nr5a2 in ovulation and luteinization in different stages of the follicle maturation, we hypothesized that Nr5a2 modulates the events leading to ovulation in a temporal sequence. By crossing Nr5a2-floxed and Cyp19-Cre mice (Nr5a2f/fCyp19Cre/+), Nr5a2 was disrupted in granulosa cells of antral and preovulatory follicles. No litters were born to Cyp19Cre-cKO females (n=4) during a 6 months breeding trial. Cyp19Cre-cKO enabled the development of a luteal-like structure, and 1-year-old females presented hemorrhagic follicular cysts and hypertrophic ovarian surface epithelium. Both knockout models display lack of cumulus expansion and ovulation. We conclude that Nr5a2 differentially regulates folliculogenesis and ovulation in granulosa cells of small and antral follicles.

Le récepteur nucléaire Nr5a2 est exprimé dans l’ovaire, plus spécifiquement dans les cellules de granulosa et lutéales. Une déplétion conditionnelle de Nr5a2 dans les cellules de granulosa au stade de follicule primaire par croisement de souris Nr5a2-flox et Amhr2-Cre (Nr5a2f/fAmhr2Cre/+) génère des problèmes au niveau de l’expansion du cumulus, de l’ovulation et de la lutéinisation. Ainsi, nous estimons que Nr5a2 régule les connexions intercellulaires dans le follicule ovarien via la connexine 43 (Cx43), une protéine de jonction impliquée dans l’expansion du cumulus. Le premier objectif de l’étude était de déterminer si l’absence d’expansion du cumulus chez les souris Amhr2Cre-cKO est liée à l’absence de communication intercellulaire adéquate entre les cellules de granulosa et de cumulus dans les follicules préovulatoires. À cette fin, des ovaires de souris immatures Amhr2Cre-cKO et non transgéniques ont été prélevés (n=3) après un traitement de superstimulation utilisant les gonadotropines eCG suivie de hCG afin d’induire l’ovulation. Nous avons ainsi démontré, par RT-PCR, une sous-expression de Cx43 avant et au moment du stimulus ovulatoire (0 h et 2 h) chez le groupe Amhr2Cre-cKO (P<0.01), ce qui pourrait mener à un problème dans l’acquisition de la compétence développementale de l’oocyte. D’un autre côté, au moment de l’ovulation (12 h), l’ARNm de Cx43 est surexprimé dans le groupe Amhr2Cre-cKO, ce qui pourrait prévenir les cellules du cumulus de se détacher l’une de l’autre. Nous avons ainsi conclu que Cx43 est un gène sous le contrôle de Nr5a2 et qu’une régulation erronée de ce gène est une cause possible du problème d’expansion du cumulus chez les souris Amhr2Cre-cKO. Afin d’examiner le rôle de Nr5a2 dans l’ovulation et la lutéinisation à différents stades de la maturation folliculaire, nous suggérons que Nr5a2 module la séquence temporelle des événements menant à l’ovulation. En croisant des souris Nr5a2-flox et Cyp19-Cre (Nr5a2f/fCyp19Cre/+), l’expression de Nr5a2 a été interrompue dans les cellules de granulosa des follicules antraux et préovulatoires. Aucune portée n’a été obtenue de ces souris (n=4) durant un essai d’accouplement de 6 mois. Chez les souris Cyp19Cre-cKO on remarque la présence de structures s’apparentant à des cellules de type lutéales et les femelles âgées d’un an présentent des kystes folliculaires hémorragiques et une hypertrophie de l’épithélium en surface de l’ovaire. Les deux modèles transgéniques démontrent donc une absence de l’expansion du cumulus et de l’ovulation. En conclusion, Nr5a2 semble réguler différemment la folliculogenèse et l’ovulation dans les cellules de granulosa des follicules primaires et antraux. / The nuclear receptor Nr5a2 is expressed in the ovary, exclusively in granulosa and luteal cells. Conditional disruption of Nr5a2 in granulosa cells beginning with primary follicles by means of Nr5a2-floxed and Amhr2-Cre mice (Nr5a2f/fAmhr2Cre/+) results in failure in cumulus expansion, ovulation and luteinization. We hypothesize that Nr5a2 regulates intercellular connections in ovarian follicles through connexin 43 (Cx43), a gap-junctional protein related to cumulus expansion. The first objective of this study was to determine whether the lack of cumulus expansion in Amhr2Cre-cKO mice is related to the absence of normal cell-to-cell communication in cumulus/granulosa cells of preovulatory follicles. To address this, immature ovaries of Amhr2Cre-cKO and non-transgenic littermates mice were collected (n=3) after superstimulation to induce follicle development and ovulation. Using RT-PCR, the Cx43 mRNA levels were shown to be downregulated prior to and at the time of the ovulatory stimulus (0 h and 2 h) in the Amhr2Cre-cKO group (P<0.01), which may lead to the failure in the acquisition of oocyte developmental competence. On the other hand, by the time of ovulation (12 h), mRNA levels of Cx43 are upregulated in Amhr2Cre-cKO group, which may prevent the cumulus cells to detach one from another. We conclude that Cx43 is one of the downstream genes under Nr5a2 control and its dysregulation can be one reason for the defect in cumulus expansion in Amhr2Cre-cKO females. To examine the role of Nr5a2 in ovulation and luteinization in different stages of the follicle maturation, we hypothesized that Nr5a2 modulates the events leading to ovulation in a temporal sequence. By crossing Nr5a2-floxed and Cyp19-Cre mice (Nr5a2f/fCyp19Cre/+), Nr5a2 was disrupted in granulosa cells of antral and preovulatory follicles. No litters were born to Cyp19Cre-cKO females (n=4) during a 6 months breeding trial. Cyp19Cre-cKO enabled the development of a luteal-like structure, and 1-year-old females presented hemorrhagic follicular cysts and hypertrophic ovarian surface epithelium. Both knockout models display lack of cumulus expansion and ovulation. We conclude that Nr5a2 differentially regulates folliculogenesis and ovulation in granulosa cells of small and antral follicles.

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