Research Areas

A major focus of the Golden Laboratory over the past 20 years has been to elucidate the role that the Aristaless-related homeodomain transcription factor (ARX) plays in normal development and how mutations result in a spectrum of human neurodevelopmental disorders. We developed a mouse line harboring a floxed Arx allele and conducted a series of experiments abrogating Arx from either cortical interneurons or projection neurons. We have been able to show that the loss of Arx from cortical interneurons gives rise to the epilepsy phenotype, while its removal from projection neurons gives rise to the structural brain defects and contributes to the behavioral phenotypes observed in patients. Some of our recent data has revealed how different mutations in this one gene can give similar neurologic phenotypes, while completely different structural defects in the brain. This is the result of ARX working in distinct transcriptional complexes in different progenitor populations. Our current work is taking a proteomics approach to define the components of these transcriptional complexes.

In the late 1990’s it was determined that the cortical interneurons are derived from the ventral ganglionic eminence as opposed to the dorsal cortical ventricular zone where it has been assumed all cortical neurons were derived. The cortical interneurons migrate from the ganglionic eminence to the cortical plate, and we have been interested in this migratory pathway. We have shown that this route of migration is perturbed in numerous models of human cell migration disorders including the Lis1 (model of human lissencephaly) mouse. We have also characterized the path on which these neurons migrate and have contributed to our understanding of the role of the attractant stromal cell-derived factor 1 (SDF1) in regulating the behavior of migrating interneurons and promoting efficient migration of cells to their targets. Most recently, we have identified a novel role for mitochondria in this migration path. Importantly, these neurons have been implicated in epilepsy and other neurocognitive disorders. Thus, we have been contributing to our understanding of these devastating disorders.

As a clinical neuropathologist, Dr. Jeffrey Golden has contributed to our understanding of human malformations through the description of human brains, including those exhibiting cell migration disorders similar to those studied in the laboratory and mentioned earlier. He has reported the largest analysis of lissencephaly brains and created diagnostic criteria that help define appropriate genetic testing. Dr. Golden has also helped better classify polymicrogyrias. His research encompasses an indepth investigation into cortical interneuron defects in human migration disorders as well as the description of novel human malformation syndromes.