Gsx Factors and the Regulation of Forebrain Development
The developmental programs of the central nervous system give rise to a myriad of neuronal and glial subtypes that are patterned by transcription factors along the dorsal-ventral and anterior-posterior axes. These diverse cellular subtypes are often localized to developmental regions, such as the lateral ganglionic eminence within the forebrain, which gives rise to the basal ganglia. The basal ganglia are a collection of neuronal structures that are important for regulating voluntary motor movement, cognition, learning and emotion.
The homeodomain transcription factor, Gsx2 is essential for mammalian basal ganglia development by regulating gene expression required for the proper patterning and differentiation of embryonic forebrain progenitors in the ventral telencephalon. Accordingly, humans homozygous for either a GSX2 null allele or a specific homeodomain variant exhibit basal ganglia dysgenesis, which correlates with their neurological symptoms that include severedystonia and intellectual impairment.
Coupled with years of research in mice from collaborator, Kenneth Campbell, PhD, these data demonstrate that Gsx2 sits atop a conserved genetic hierarchy controlling basal ganglia development. To define how Gsx2 regulates forebrain progenitor gene expression during basal ganglia development, the Gebelein and Campbell labs recently used the CUT&RUN assay to map the genomic regulatory elements bound by Gsx2 in the mouse LGE, many of which are located near key genes required for basal ganglia development.
Moreover, we have made a mouse model with the disease-causing human variant as well as inducible human ESC models (in collaboration with Jason Tchieu, PhD) to assess how GSX2 regulates neural development. Armed with these novel reagents and methods, we are now in a strong position to utilize our research team’s collective strengths in genetics, functional genomics, biochemistry, and bioinformatics to determine how Gsx2 controls progenitor gene expression during basal ganglia development, and to model how the human GSX2 homeodomain disease variant alters the regulation of these essential gene regulatory networks.
