An In Vivo Drug Screen Reveals That Sirtuin 2 Activity Promotes Spinal Cord Neurogenesis in Developing Zebrafish

Neurogenesis plays a fundamental role in the development of a functional nervous system. Seeking to uncover molecules and signalling pathways involved in spinal cord neurogenesis, we recently designed a drug screening protocol in developing zebrafish (González-Llera et al., 2024). Here, we have expanded this drug screen and discovered a previously unknown role of the deacetylase sirtuin 2 (SIRT2) in promoting the generation of serotonergic interneurons in the spinal cord. Treatments with specific SIRT2 inhibitors reduced the generation of serotonergic neurons in the spinal cord, which led to locomotor deficits. Our data suggest that SIRT2 regulates mitotic activity in progenitor cells to promote the generation of serotonergic neurons in developing animals. Together, our results uncover SIRT2 as a key regulator of spinal cord neurogenesis and position it as a promising target for strategies aimed at neural repair in spinal cord disorders.