Biology subjects

Mason, J. O.

Publications and source records attributed to Mason, J. O..

3 recordsLinked to original sources

bioRxiv2024

GABA/Glutamate neuron differentiation imbalance and increased AKT/mTOR signalling in CNTNAP2-/-cerebral organoids.

We developed a human cerebral organoid model derived from induced pluripotent stem cells (iPSCs) with targeted genome editing to abolish protein expression of the Contactin Associated Protein-like 2 (CNTNAP2) autism spectrum disorder (ASD) risk gene, mimicking loss-of-function mutations seen in patients. CNTNAP2-/- cerebral organoids displayed accelerated cell cycle, ventricular zone disorganisation and increased cortical folding. Proteomic analysis revealed disruptions in Glutamatergic/GABAergic synaptic pathways and neurodevelopment, highlighting increased protein expression of corticogenesis and neurodevelopment-related genes such as Forkhead box protein G1 (FOXG1) and Paired box 6 (PAX6). Transcriptomic analysis revealed differentially expressed genes (DEG) belonging to inhibitory neuron-related gene networks. Interestingly, there was a weak correlation between the transcriptomic and proteomic data, suggesting nuanced translational control mechanisms. Along these lines we found upregulated Protein Kinase B (Akt)/mechanistic target of rapamycin (mTOR) signalling in CNTNAP2-/- organoids. Spatial transcriptomics analysis of CNTNAP2-/- ventricular-like zones demonstrated pervasive changes in gene expression, particularly in PAX6- cells, implicating upregulation of cell cycle regulation pathways, synaptic and Glutamatergic/GABAergic pathways. We noted a significant overlap of all D30 cerebral organoids omics datasets with an idiopathic ASD (macrocephaly) iPSC-derived telencephalic organoids DEG dataset, where FOXG1 was upregulated. Moreover, we detected increased Glutamate decarboxylase 1 (GAD1) and decreased T-Box Brain Transcription Factor 1 (TBR1) expressing cells, suggesting altered GABAergic/Glutamatergic neuron development. These findings potentially highlight a shared mechanism in the early cortical development of various forms of ASD, further elucidate the role of CNTNAP2 in ASD pathophysiology and cortical development and pave the way for targeted therapies using cerebral organoids as preclinical models.

neuroscience↗

bioRxiv2023

Loss of PAX6 alters the excitatory/inhibitory neuronal ratio in human cerebral organoids

The transcription factor PAX6 is a crucial regulator of multiple aspects of embryonic forebrain development. It has well-established roles in the regulation of excitatory and inhibitory neuron development in the embryonic cortex in mice but PAX6s roles during human forebrain development are less well understood. Using human cerebral organoids, we investigated PAX6s roles in human neurodevelopment. Homozygous PAX6 mutant (PAX6-/-) organoids were larger than controls and contained increased inhibitory cell types. Excitatory neurons were still generated in PAX6-/- organoids but they were less mature, and a subset showed dysregulated expression of inhibitory identity genes compared to PAX6+/+ controls. The inhibitory cells found in PAX6-/- organoids physically segregated from excitatory neurons and presented a distinct transcriptomic profile when compared to in vivo cortical inhibitory neurons. PAX6-/- organoids showed a dysregulated cellular response to PTN-PTPRZ1 signalling, which contributed to the observed increase in inhibitory neurons and the consequent altered excitatory to inhibitory neuronal ratio. Summary StatementHuman cerebral organoids lacking PAX6 expression show an altered excitatory to inhibitory neuronal ratio, concomitant with altered responses to intercellular PTN-PTPRZ1 signalling.

developmental biology↗

bioRxiv2018

Tissue-specific actions of Pax6 on proliferation-differentiation balance in the developing forebrain are Foxg1-dependent

Differences in the growth and maturation of diverse forebrain tissues depends on region-specific transcriptional regulation. Individual transcription factors act simultaneously in multiple regions that develop very differently, raising questions about the extent to which their actions vary regionally. We found that the transcription factor Pax6 affects the transcriptomes and the balance between proliferation and differentiation in opposite directions in murine diencephalon versus cortex. We tested several possible mechanisms to explain Pax6s tissue-specific actions and found that the presence of the transcription factor Foxg1 in cortex but not diencephalon was most influential. We found that Foxg1 is responsible for many of the differences in cell cycle gene expression between diencephalon and cortex. In cortex lacking Foxg1, Pax6s action on the balance of proliferation versus differentiation became diencephalon-like. Our findings reveal a mechanism for generating regional forebrain diversity in which the actions of one transcription factor completely reverse the actions of another.

developmental biology↗