A5075745937- Neuroscience and Neuropharmacology Research
- Genetics and Neurodevelopmental Disorders
- Pluripotent Stem Cells Research
- Renal and related cancers
- CRISPR and Genetic Engineering
- Neuroscience and Neural Engineering
- Genomics and Rare Diseases
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Neurogenesis and neuroplasticity mechanisms
- RNA modifications and cancer
- Ion channel regulation and function
- Receptor Mechanisms and Signaling
- Sexual Differentiation and Disorders
- Epilepsy research and treatment
- RNA Research and Splicing
- RNA regulation and disease
- Amino Acid Enzymes and Metabolism
- RNA and protein synthesis mechanisms
- Photoreceptor and optogenetics research
- Urological Disorders and Treatments
- Mitochondrial Function and Pathology
- Anesthesia and Neurotoxicity Research
- Autism Spectrum Disorder Research
- Organ Donation and Transplantation
- Circular RNAs in diseases
Florey Institute of Neuroscience and Mental Health
2018-2024
Murdoch Children's Research Institute
2020-2024
The University of Melbourne
2019-2024
Royal Children's Hospital
2023
Ruhr University Bochum
2010-2018
De novo variation in SCN2A can give rise to severe childhood disorders. Biophysical gain of function is seen some patients with early seizure onset developmental and epileptic encephalopathy (DEE). In these cases, targeted reduction expression could substantially improve clinical outcomes. We tested this theory by central administration a gapmer antisense oligonucleotide (ASO) targeting Scn2a mRNA mouse model DEE (Q/+ mice). Untreated Q/+ mice presented spontaneous seizures at P1 did not...
Abstract Premature ovarian insufficiency (POI) is a common cause of infertility in women, characterised by amenorrhea and elevated FSH under the age 40 years. In some cases, POI syndromic association with other features such as sensorineural hearing loss Perrault syndrome. heterogeneous disease over 80 causative genes known so far; however, these explain only minority cases. Using whole-exome sequencing (WES), we identified MRPL50 homozygous missense variant (c.335T > A; p.Val112Asp)...
Currently an in vitro model that fully recapitulates the human embryonic gonad is lacking. Here we describe a defined feeder-free protocol to generate early testis-like cells with ability be cultured as organoid, from induced pluripotent stem cells. This stepwise approach uses small molecules mimic development, upregulation of bipotential markers (LHX9, EMX2, GATA4, and WT1) at day 10 culture, followed by induction testis Sertoli cell (SOX9, WT1, AMH) 15. Aggregation into 3D structures...
Abstract Squamous cell carcinoma antigen recognized by T cells 3 ( SART3 ) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in nine individuals presenting intellectual disability, global developmental delay and a subset of brain anomalies, together gonadal dysgenesis 46,XY individuals. Knockdown Drosophila orthologue reveals conserved role testicular neuronal development. Human induced...
Abstract De novo variants in the Na V 1.2 voltage‐gated sodium channel gene SCN2A are among major causes of developmental and epileptic encephalopathies (DEE). Based on their biophysical impact conductance gating, DEE can be classified into gain‐of‐function (GoF) or loss‐of‐function (LoF). Clinical functional data have linked early seizure onset to GoF variants, whereas late is associated with loss function. This study aims assess LoF cultured neuronal network activity explore modulation by...
The majority of AMPA receptors in the adult brain contain GluA2 subunits, which can be edited at Q/R site, changing a glutamine to an arginine within ion pore. editing renders AMPARs virtually Ca2+-impermeable, is important for normal receptor function. Thus, all subunits are Q/R-edited brain. However, it has remained controversial precisely when sets during development. In present study, we show that mRNA very rapidly immediately after its appearance, 4.5 days differentiation from 46C...
The absence of expression the Y-chromosome linked testis-determining gene SRY in early supporting gonadal cells (ESGC) leads bipotential gonads into ovarian development. However, genetic variants NR2F2, encoding three isoforms transcription factor COUP-TFII, represent a novel cause SRY-negative 46,XX testicular/ovotesticular differences sex development (T/OT-DSD). Thus, we hypothesized that COUP-TFII is part developmental network. known to be expressed interstitial/mesenchymal giving rise...
Determining the mechanism of action (MOA) novel or naturally occurring compounds mostly relies on assays tailored for individual target proteins. Here we explore an alternative approach based pattern matching response profiles obtained using cultured neuronal networks. Conolidine and cannabidiol are plant-derivatives with known antinociceptive activity but unknown MOA. Application conolidine/cannabidiol to networks altered network firing in a highly reproducible manner created similar impact...
Abstract The clinical spectrum associated with SCN2A de novo mutations (DNMs) continues to expand and includes autism disorder or without seizures, in addition early late seizure onset developmental epileptic encephalopathies (DEEs). Recent biophysical studies on variants suggest that the majority of DEE DNMs cause gain function. Gain function SCN2A, principal sodium channel excitatory pyramidal neurons, would result heightened neuronal activity is likely underlie pathology seen patients....
The NR2F2 gene encodes the transcription factor COUP-TFII, which is upregulated in embryonic mesoderm. Heterozygous variants cause a spectrum of congenital anomalies including cardiac and gonadal phenotypes. We generated heterozygous (MCRIi030-A-1) homozygous (MCRIi030-A-2) NR2F2-knockout induced pluripotent stem cell (iPSC) lines from human fibroblasts using one-step protocol for CRISPR/Cas9 gene-editing episomal-based reprogramming. Both iPSC exhibited normal karyotype, typical morphology,...
Glutamate and its receptors are ascribed a pivotal role during acitivity-dependent neurogenesis. Nevertheless, their precise expression patterns embryonic adult differentiation remain elusive. An in vitro-approach that includes cells representing as well neural stem both amenable to retinoic acid treatment is well-suited for assessing the developmental regulation of ionotropic glutamate (iGluRs). The chosen system provides continuous time line from neurogenesis via two distinguishable cell...
SCN2A encodes Na V 1.2, an excitatory neuron voltage-gated sodium channel and a major monogenic cause of neurodevelopmental disorders, including developmental epileptic encephalopathies (DEE) autism. Clinical presentation pharmocosensitivity vary with the nature variant dysfunction can be divided into gain-of-function (GoF) cases pre- or peri-natal seizures loss-of-function (LoF) patients typically having infantile spasms after 6 months age. We established assessed patient induced...
Ionotropic glutamate receptors (iGluRs) do not only mediate the majority of excitatory neurotransmission in vertebrate CNS, but also modulate pre- and postnatal neurogenesis. Most studies on developmental role iGluRs are performed neural progenitors stem cells (NSCs). We took a step back our study by examining earliest possible cell type, embryonic (ESCs), looking at mRNA expression major iGluR subfamilies undifferentiated mouse ESCs. For that, we used two distinct murine ES lines, 46C ESCs...
The transcription factor WT1 plays a critical role in several embryonic developmental processes such as gonadogenesis, nephrogenesis, and cardiac development. We generated homozygous (MCRIi031-A-3) knockout induced pluripotent stem cell (iPSC) line from human fibroblasts using one-step protocol for CRISPR/Cas9 gene-editing episomal-based reprogramming. cells exhibit normal karyotype morphology, express pluripotency markers, have the capacity to differentiate into three germ layers. These...
The transcription factor SOX9 plays a critical role in several embryonic developmental processes such as gonadogenesis, chrondrogenesis, and cardiac development. We generated heterozygous (MCRIi031-A-1) homozygous (MCRIi031-A-2) knockout induced pluripotent stem cell (iPSC) lines from human fibroblasts using one-step protocol for CRISPR/Cas9 gene-editing episomal-based reprogramming. Both iPSC exhibit normal karyotype morphology, express pluripotency markers, have the capacity to...
Abstract SCN2A encodes Na V 1.2, an excitatory neuron voltage-gated sodium channel and major monogenic cause of neurodevelopmental disorders, including developmental epileptic encephalopathies (DEE) autism. Clinical presentation pharmocosensitivity vary with nature variant dysfunction gain-of-function (GoF) cases presenting pre- or peri-natal seizures loss-of-function (LoF) patients typically having infantile spasms after 6 months age. Here, we established assessed patient induced...
Abstract The absence of expression the Y-chromosome linked testis-determining gene SRY in early supporting gonadal cells (ESGC) bipotential gonads leads to ovarian development. However, genetic variants NR2F2 /COUP-TFII represent a novel cause -negative 46,XX testicular/ovotesticular differences sex development (T/OT-DSD). Thus, we hy-pothesized that COUP-TFII is part developmental network. We examined and network under its regulation human by analyzing single cell RNA-sequencing datasets...