Biology subjects

Duncan, R.

Publications and source records attributed to Duncan, R..

3 recordsLinked to original sources

bioRxiv2025

The Short Isoform of the Mouse Actin Adaptor Protein Synaptopodin-2 Activates Actin-Responsive Transcription Factors and Enhances Myoblast Fusion

Expression of synaptopodin-2 (SYNPO2), an actin cytoskeleton adaptor protein, is up-regulated following myoblast differentiation into myocytes and subsequently myotubes but no functional role in muscle development has been attributed to SYNPO2. We now show that of the three known mouse SYNPO2 isoforms, only the shortest isoform, SYNPO2As, is upregulated following differentiation of C2C12 myoblasts and primary mouse muscle satellite cells. Consistent with the differentiation-dependent expression pattern of these different isoforms, ectopic expression of SYNPO2As significantly increased myotube formation while the two large SYNPO2 isoforms (SYNPO2A or SYNPO2B) inhibited myocyte fusion into multinucleated myotubes. Irrespective of the fusion phenotype, all three isoforms enhanced migration of differentiating myoblasts. Knockdown studies using shRNA confirmed a pro-myogenic role for the short SYNPO2As isoform. Interestingly, SYNPO2As-transduced cells increased the transcript levels of late myogenic differentiation markers in the STARS (striated muscle activator of Rho signaling) and SRF (serum response factor) pathways that correlated with the enhanced fusion phenotype. These results identify the actin adaptor protein SYNPO2As as a new pro-myogenic factor that upregulates late myogenic differentiation markers and myotube formation.

developmental biology↗

bioRxiv2023

Glutathione supports lipid abundance in vivo

Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are reported to be highest in liver tissue, which is also a hub for lipid production. While the loss of GSH did not cause liver failure, it decreased lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we found that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the livers balance of redox buffering and triglyceride production.

biochemistry↗

bioRxiv2018

Powerful and Efficient Strategies for Genetic Association Testing of Symptom and Questionnaire Data in Psychiatric Genetic Studies

Genetic studies of psychiatric disorders often deal with phenotypes that are not directly measurable. Instead, researchers rely on multivariate symptom data from questionnaires and surveys like the PTSD Symptom Scale (PSS) and Beck Depression Inventory (BDI) to indirectly assess a latent phenotype of interest. Researchers subsequently collapse such multivariate questionnaire data into a univariate outcome to represent a surrogate for the latent phenotype. However, when a causal variant is only associated with a subset of collapsed symptoms, the effect will be challenging to detect using the univariate outcome. We describe a more powerful strategy for genetic association testing in this situation that jointly analyzes the original multivariate symptom data collectively using a statistical framework that compares similarity in multivariate symptom-scale data from questionnaires to similarity in common genetic variants across a gene. We use simulated data to demonstrate this strategy provides substantially increased power over standard approaches that collapse questionnaire data into a single surrogate outcome. We also illustrate our approach using GWAS data from the Grady Trauma Project and identify genes associated with BDI not identified using standard univariate techniques. The approach is computationally efficient, scales to genome-wide studies, and is applicable to correlated symptom data of arbitrary dimension (thereby aligning with National Institute of Mental Healths Research Domain Criteria).

genetics↗