LMP student seminars: 21 October
Each week during term time, MSc and PhD candidates in the Department of Laboratory Medicine and Pathobiology present their research.
Anyone is welcome. No need to register.
Location: Medical Sciences Building, rooms 4171 or 4279, see below.
As part of the core research curriculum, students taking LMP1001/2/3: Graduate Seminars in Laboratory Medicine and Pathobiology will present their projects. Please see abstracts below.
1. Brain and Neuroscience
Location: MSB 4279
Jarryll Uy
- Title: Modelling the neurodevelopmental impact of the autism gene SCN2A using human neural organoids
- Supervisor: Dr. Karun Singh
Alexandra Moffat
- Title: Proneural genes form a combinatorial code to diversify neocortical neural progenitor cells
- Supervisor: Dr. Carol Schuurmans
Abstracts
Jarryll Uy: Modelling the neurodevelopmental impact of the autism gene SCN2A using human neural organoids
Voltage-gated sodium channels regulate neuronal excitability and fast synaptic transmission in the postnatal and adult brain. The gene SCN2A, encoding the sodium channel Nav1.2, regulates synaptic development and variants in SCN2A are associated with autism spectrum disorders (ASD). The expression pattern of SCN2A begins during fetal cortical development, prior to the onset of synaptic transmission, but it is unknown whether SCN2A regulates early cortical development through mechanisms independent of synaptic transmission. Here we reveal that isogenic and ASD patient-derived human forebrain organoids modelling a loss of SCN2A function display impaired excitatory and inhibitory neurogenesis, leading to a developmental imbalance. Unexpectedly, we find precocious generation of cortical inhibitory neurons is driven by elevated sonic hedgehog (SHH) signaling and is reversible through pharmacological inhibition. Functionally, these developmental phenotypes arise due to sodium channel dysfunction and lead to abnormal neuronal network activity. Our results identify a new mechanisim for cortical excitatory and inhibitory neurogenesis involving SCN2A, and reveal that early neurogenesis deficits precedes postnatal neural circuit dysfunction in SCN2A-associated disorders.
Alexandra Moffat: Proneural genes form a combinatorial code to diversify neocortical neural progenitor cells
During development, the neocortical neural progenitor cell (NPC) pool is molecularly heterogeneous and the genes conferring their distinct fates are poorly understood. Here, we identify a proneural gene combinatorial code that diversifies cortical NPCs. scRNA-seq data was mined from murine embryonic and early postnatal cortices to generate trajectory inference models. We found that the predominant proneural gene, Neurog2, is transiently co-expressed with Ascl1 and/or Neurog1 in NPCs with early pseudotime identities that are undergoing apical-to-basal transitions. Neurog2/Ascl1 reporter mice, expressing unique reporters, were used to examine whether proneural gene pairs confer distinct identities. We revealed that NPCs have distinct cell division modes and cell cycle dynamics depending on their proneural gene profile. To assess Neurog2/Neurog1 interactions and determine their specific requirement for the production of early born neurons and maintenance of NPCs, we used double knockouts and novel split-Cre transgenics crossed to a Rosa-diphtheria-toxin-A line to selectively ‘delete’ double+ cells. Finally, we identified the requirement of Neurog1/Neurog2 for Bcl11b and Nhlh2 expression in early-born neurons by performing in silico mutation of a cortical Neurog2-gene regulatory network, which we validated with Neurog1/Neurog2 mutant and ‘deleter’ mice. Together, our data illustrates how proneural genes act combinatorically to diversify gene regulatory networks and therefore, restrict NPC lineages and create cortical neuronal diversity.
Contact
No need to register.
Contact lmp.grad@utoronto.ca with any questions