Biology subjects

Bunt, J.

Publications and source records attributed to Bunt, J..

5 recordsLinked to original sources

bioRxiv2025

C12ORF57: a novel principal regulator of synaptic AMPA currents and excitatory neuronal homeostasis

ObjectiveExcitatory neuronal homeostasis is crucial for neuronal survival, circuit function, and plasticity. Disruptions in this form of homeostasis are believed to underpin a variety of neuronal conditions including intellectual disability, epilepsy, and autism. However, the underlying genetic and molecular mechanisms maintaining this homeostasis remain poorly understood. Biallelic recurrent loss of function mutations in C12ORF57, an evolutionarily conserved X amino acid novel open reading frame, underlie Temtamy syndrome (TS)--a neurodevelopmental disorder characterized by epilepsy, dysgenesis of the corpus callosum, and severe intellectual disability. MethodsThrough multiple lines of inquiry, we establish that C12ORF57/GRCC10 plays an unexpected central role in synaptic homeostatic downscaling in response to elevated activity, uncovering a novel mechanism for neuronal excitatory homeostasis. To probe these mechanisms, we developed a new knockout (KO) mouse model of the genes murine ortholog, Grcc10 as well as cellular and in vitro assays. ResultsGrcc10 KO mice exhibit the characteristic phenotypic features seen in human TS patients, including increased epileptiform activity. Corresponding with the enhanced seizure susceptibility, hippocampal neurons in these mice exhibited significantly increased AMPA receptor expression levels and higher amplitude of miniature excitatory postsynaptic currents (mEPSCs). We further found that GRCC10/C12ORF57 modulates the activity of calcium/calmodulin dependent kinase 4 (CAMK4) and thereby regulates the expression of CREB and ARC. InterpretationOur study suggests through this novel mechanism, deletion of Grcc10 disrupts the characteristic synaptic AMPA receptor downscaling that accompanies increased activity in glutamatergic neurons.

neuroscience↗

bioRxiv2021

EMX2 transcriptionally regulates Nfib expression in neural progenitor cells during early cortical development.

The nuclear factor one (NFI) transcription factors play key roles in regulating the onset of both neuronal and glial differentiation during cortical development. Reduced NFI expression results in delayed differentiation, which is associated with neurodevelopmental disorders in humans that include intellectual disability, agenesis of the corpus callosum and macrocephaly. Despite their importance, our understanding of how individual NFI family members are regulated during cortical development remains limited. Here, we demonstrate that in mice, the homeobox transcription factor EMX2 regulates Nfib expression in radial glial cells during cortical development. Using a combination of bioinformatics, molecular and histological approaches, we demonstrate that EMX2 is able to bind to the Nfib promoter to up-regulate Nfib expression. Unexpectedly, in vivo over-expression of EMX2 in wildtype animals does not further up-regulate NFIB but instead leads to its down-regulation. Therefore, our findings suggest that EMX2 is capable of both activating and repressing Nfib, in a context-dependent manner. This bi-directional control over Nfib expression enables fine-tuning of the total level of NFI proteins expressed and could be important for cell-type specific NFI functions.

neuroscience↗

bioRxiv2020

DRAXIN regulates interhemispheric fissure remodelling to influence the extent of corpus callosum formation

Corpus callosum dysgenesis (CCD) is a congenital disorder that incorporates either partial or complete absence of the largest cerebral commissure. Remodelling of the interhemispheric fissure (IHF) provides a substrate for callosal axons to cross between hemispheres, and its failure is the main cause of complete CCD. However, it is unclear whether defects in this process could give rise to the heterogeneity of expressivity and phenotypes seen in human cases of CCD. We identify incomplete IHF remodelling as the key structural correlate for the range of callosal abnormalities in inbred and outcrossed BTBR mouse strains, as well as in humans with partial CCD. We identify an eight base pair deletion in Draxin and misregulated astroglial and leptomeningeal proliferation as genetic and cellular factors for variable IHF remodelling and CCD in BTBR acallosal strains. These findings support a model where genetic events determine corpus callosum structure by influencing leptomeningeal-astroglial interactions at the IHF.

neuroscience↗

bioRxiv2019

Transcription factors NFIA and NFIB induce cellular differentiation high-grade astrocytoma

Astrocytomas are composed of heterogeneous cell populations. Compared to grade IV glioblastoma, low-grade astrocytomas have more differentiated cells and are associated with a better prognosis. Therefore, inducing cellular differentiation may serve as a therapeutic strategy. The nuclear factor one (NFI) transcription factors are essential for normal astrocytic differentiation and therefore could be effectors of cellular differentiation in glioblastoma. We analysed expression of family members NFIA and NFIB using high-grade astrocytoma mRNA expression datasets, and with immunofluorescence co-staining. Their expression is reduced in glioblastomas and is associated with differentiated and mature astrocyte-like cells at a cellular level. Furthermore, induction of NFI expression is sufficient to promote cellular differentiation in patient-derived glioblastoma xenografts. Our findings indicate that NFI proteins may have an endogenous pro-differentiative function in astrocytomas, similar to their role in normal development. Overall, our study establishes a basis for further investigation of targeting NFI-mediated differentiation as a potential differentiation therapy.

cancer biology↗

bioRxiv2018

Pathogenic DDX3X mutations impair RNA metabolism and neurogenesis during fetal cortical development

De novo germline mutations in the RNA helicase DDX3X account for 1-3% of unexplained intellectual disability (ID) cases in females, and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here we use human and mouse genetics, and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n=78), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuronal generation and migration. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity and induce ectopic RNA-protein granules and aberrant translation in neural progenitors and neurons. Together, our study demonstrates novel mechanisms underlying DDX3X syndrome, and highlights roles for RNA-protein aggregates in the pathogenesis of neurodevelopmental disease.

genetics↗