Enhancing WNT Signaling Restores Cortical Neuronal Spine Maturation and Synaptogenesis in Tbr1 Mutants
Journal: Cell Reports Publication year: 2020
This is an article I found to be very intriguing, as one of my colleagues when I was at McMaster University, Dr. Karun Singh (soon relocating to the Krembil Brain Insitute in Toronto), studies Autism Spectrum Disorder (ASD), and I had the pleasure of discussing his research with him and his trainees on many occasions. TBR1 (T-box brain transcription factor 1) is a T-box transcription factor in the same family as Brachyury (the original T-box factor), which my lab knows well as a Wnt/β-catenin target gene in embryonic stem cells. Whereas Brachyury regulates mesodermal differentiation, TBR1 plays a critical role in brain development, both pre- and postnatally and is a high-confidence ASD risk gene. The authors had previously shown that TBR1 is required for maintaining corticothalamic identity and synaptogenesis through their studies with conditional knockout mice targeting TBR1 during neonatal development. Here, Fazel Darbandi et al., by employing the same neonatal-specific conditional knockout mouse, report that TBR1 regulates transcriptional circuits in specific cortical brain layers to promote dendritic spine and synaptic density. Of interest to a Wnt signaling fan like me, Wnt signaling is required for proper TBR1 neurodevelopmental function, as Wnt7b is a target gene of TBR1 in a neonatal neurodevelopmental context. The authors show that augmenting Wnt/β-catenin signaling by employing the GSK-3 inhibitors LiCl or SB216763 can ameliorate the effects of TBR1 knockout on dendritic spine and synaptic density. As an aside, please note that SB216763 is not a GSK-3β-specific inhibitor, it will also inhibit GSK-3ɑ.