John Rubenstein

Biosketch

John Rubenstein is a developmental geneticist recognized for his work elucidating mechanisms that generate forebrain regions and cell types. He is particularly known for defining the subcortical source, and tangential migration, of cortical inhibitory neurons. Rubenstein grew up near Stanford University, where his father was on the medical faculty. He was a chemistry major at Stanford (1973-77). As an MD, PhD student at Stanford he earned a doctorate in Biophysics (1982) for studies on the effect of cholesterol on the motions of phospholipids in membranes, and for studies on the biogenesis of plasma membrane proteins (with Harden McConnell and James Rothman). As a postdoctoral fellow at the Pasteur Institute (1984-86; with Francois Jacob, J.F. Nicolas, Josh Sanes) he showed that antisense RNA can inhibit gene expression, and he developed retroviral vectors for gene delivery and fate mapping. As a resident physician in Child Psychiatry at Stanford (1986-1991; with Roland Ciaranello), he identified genes that are preferentially expressed in the embryonic forebrain, and he has worked on this subject as a faculty member at UCSF ever since. He is a member of the National Academy of Sciences, the National Academy of Medicine and the American Academy of Arts and Sciences.

Research Interests

We focus on transcriptional regulation (TR) at the genome level of regional and cell type specification in the cerebral cortex and basal ganglia to define transcriptional circuits that control these processes and to explore their relevance to human disorders. Having discovered that most cortical interneurons are generated at a distance source, the MGE, our work has also focused on the cell biological, transcriptional and cell-surface signaling mechanisms regulating their specification, migration and synaptogenesis and function. With UCSF colleagues we provided evidence that transplantation of immature MGE-derived interneurons ameliorates epilepsy in mice. This has led to the foundation of a company named Neurona dedicated to generating human MGE-derived interneurons to treat human epilepsy. Finally, we study TRs that are disease genes such as Tbr1 and Pogz that cause intellectual disability and autism, or Dlx1/2/5 and Maf/Mafb that can cause seizures in mice. These TRs have sequential functions in cell specification/differentiation and later in neuronal connectivity and function. We are attempting to derive transcriptional circuits that function while immature neurons are forming synapses. Recent evidence shows that Tbr1 promotes mouse synapse development on cortical excitatory neurons through promoting WNT signaling; conversely increasing WNT signaling rescues in Tbr1-/- synaptic deficits.